Antiviral compositions

ABSTRACT

The present invention is concerned with pharmaceutical compositions of antiviral compounds which can be administered to a mammal, in particular a human, suffering from a viral infection. These compositions comprise particles obtainable by melt-extruding a mixture comprising one or more antiviral compounds and one or more appropriate water-soluble polymers and subsequently milling said melt-extruded mixture.

This application is a continuation of application U.S. Ser. No.10/088,805, filed Aug. 31, 2000, now U.S. Pat. No. 7,241,458, issuedJul. 10, 2007; which in turn was a 35 USC 371 national filing ofPCT/EP00/08522 filed Aug. 31, 2000 claiming priority from EPO99.203.128.6, filed Sep. 24, 1999.

The present invention concerns pharmaceutical compositions of antiviralcompounds which can be administered to a mammal, in particular a human,suffering from a viral infection. These compositions comprise particlesobtainable by melt-extruding a mixture comprising one or more antiviralcompounds and one or more appropriate water-soluble polymers andsubsequently milling said melt-extruded mixture.

The antiviral compounds constituting the pharmaceutical compositions ofthe present invention are dispersed in a carrier by melt-extrusion toobtain a solid dispersion in order to improve their bio-availability.

Compounds structurally related to the present antiviral compounds aredisclosed in the prior art.

-   Pharmazie (1990), 45(4), p 284 discloses trisubstituted derivatives    of 2,4,6-trichloro-1,3,5-triazine having anti-bacterial activity.-   Chem. Abstr. (1990), 112, no. 1 concerns synthesis of fluorinated    derivatives of 1,3,5-triazine as potential bactericidal agents.-   Chem. Abstr. (1988), 108, no. 15 describes 2,4,6-mixed functional    substituted 1,3,5-triazines as anti-convulsives.-   Chem. Abstr. (1983), 98, no. 11 concerns the preparation of    p-(2,4-diarylamino-6-S-triazinylamino)-benzaldehyde/acetophenone    thiosemicarbazones as potential tuberculostatic agents.-   Chem. Abstr. (1981), 95, no. 4 describes the preparation of    polypyromellitimides containing dialkylamino-type melamine units.-   Chem. Abstr. (1975), 83, no. 23 describes optically active    S-triazine derivatives.-   FR-A-2099730 concerns diamino-, and dinitro-S-triazines, which can    be used for the preparation of polymeric material and colorants.-   EP-A-0795549 discloses bis-aryloxy(amino)-triazinyl-oxy(amino)aryl    derivatives as antiviral agents.-   Ashley et al. (J. Chem. Soc. (1960), January 1, pp 4525-4532)    describes amidinoanilino-1,3,5-triazines having potential    trypanocidal activity.-   WO 91/18887 discloses diaminopyrimidines as gastric acid secretion    inhibitors.-   EP-A-0588762 concerns the use of N-phenyl-2-pyrimidinamine    derivatives as proteinkinase C-inhibitors and anticancer agents.-   WO 95/10506 describes N-alkyl-N-aryl-pyrimidinamines and derivatives    thereof as Corticotropin Releasing Factor receptor antagonists.-   EP-A-0270111 discloses pyrimidine derivatives as fungicides in    agricultural and horticultural compositions.-   J. Med. Chem. (1969), 10, pp 974-975 describes    2,4-bis(arylamino)-5-methyl-pyrimidines and Chem. Abstr. (1981), 95,    no. 11 describes 2,4-bis(arylamino)-6-methylpyrimidines as    antimicrobial agents.-   J. Med. Chem. (1996), 39, pp 4358-4360 deals with    4-anilino-aminopyrimidines as non-peptide high affinity human    Cortocotropin Releasing Factor, receptor antagonists.-   EP-0,834,507 discloses substituted diamino 1,3,5-triazine    derivatives having HIV replication inhibiting properties.

The particles of the present invention consist of a solid dispersioncomprising (a) an antiviral compound of formula

a N-oxide, a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof, wherein

-   Y is CR⁵ or N;-   A is CH, CR⁴ or N;-   n is 0, 1, 2, 3 or 4;-   Q is —NR¹R² or when Y is CR⁵ then Q may also be hydrogen;-   R¹ and R² are each independently selected from hydrogen, hydroxy,    C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl,    C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- or di(C₁₋₁₂alkyl)amino,    mono- or di(C₁₋₁₂alkyl)aminocarbonyl wherein each of the    aforementioned C₁₋₁₂alkyl groups may optionally and each    individually be substituted with one or two substituents each    independently selected from hydroxy, C₁₋₆alkyloxy,    hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl, cyano, amino,    imino, aminocarbonyl, aminocarbonylamino, mono- or    di(C₁₋₆alkyl)amino, aryl and Het; or-   R¹ and R² taken together may form pyrrolidinyl, piperidinyl,    morpholinyl, azido or mono- or di(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene;-   R³ is hydrogen, aryl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,    C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with    C₁₋₆alkyloxycarbonyl; and-   each R⁴ independently is hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy,    cyano, amino carbonyl, nitro, amino, trihalomethyl,    trihalomethyloxy, or when Y is CR⁵ then R⁴ may also represent    C₁₋₆alkyl substituted with cyano or aminocarbonyl;-   R⁵ is hydrogen or C₁₋₄alkyl;-   L is —X¹—R⁶ or —X²-Alk-R⁷ wherein    -   R⁶ and R⁷ each independently are phenyl or phenyl substituted        with one, two, three, four or five substituents each        independently selected from halo, hydroxy, C₁₋₆alkyl,        C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl,        cyano, nitro, amino, and trifluoromethyl; or when Y is CR⁵ then        R⁶ and R⁷ may also be selected from phenyl substituted with one,        two, three, four or five substituents each independently        selected from aminocarbonyl, trihalomethyloxy and trihalomethyl;        or when Y is N then R⁶ and R⁷ may also be selected from indanyl        or indolyl, each of said indanyl or indolyl may be substituted        with one, two, three, four or five substituents each        independently selected from halo, hydroxy, C₁₋₆alkyl,        C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl,        cyano, nitro, amino, and trifluoromethyl; when R⁶ is optionally        substituted indanyl or indolyl, it is preferably attached to the        remainder of the molecule via the fused phenyl ring. For        instance, R⁶ is suitably 4-, 5-, 6- or 7-indolyl;    -   X¹ and X² are each independently —NR³—, —NH—NH—, —N═N—, —O—,        —S—, —S(═O)— or —S(═O)₂—;    -   Alk is C₁₋₄alkanediyl; or-   when Y is CR⁵ then L may also be selected from C₁₋₁₀alkyl,    C₃₋₁₀alkenyl, C₃₋₁₀alkynyl, C₃₋₇cycloalkyl, or C₁₋₁₀alkyl    substituted with one or two substituents independently selected from    C₃₋₇cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl,    indanyl and indolyl may be substituted with one, two, three, four or    where possible five substituents each independently selected from    halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl,    C₁₋₆alkyloxycarbonyl, formyl, nitro, amino, trihalomethyl,    trihalomethyloxy and C₁₋₆alkylcarbonyl;-   aryl is phenyl or phenyl substituted with one, two, three, four or    five substituents each independently selected from halo, C₁₋₆alkyl,    C₁₋₆alkyloxy, cyano, nitro and trifluoromethyl;-   Het is an aliphatic or aromatic heterocyclic radical; said aliphatic    heterocyclic radical is selected from pyrrolidinyl, piperidinyl,    homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and    tetrahydrothienyl wherein each of said aliphatic heterocyclic    radical may optionally be substituted with an oxo group; and said    aromatic heterocyclic radical is selected from pyrrolyl, furanyl,    thienyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein    each of said aromatic heterocyclic radical may optionally be    substituted with hydroxy;    or    -   an antiviral compound of formula

the N-oxides, the pharmaceutically acceptable addition salts, quaternaryamines and the stereochemically isomeric forms thereof, wherein-b¹=b²—C(R^(2a))=b³-b⁴= represents a bivalent radical of formula—CH═CH—C(R^(2a))═CH—CH═  (b-1);—N—CH—C(R^(2a))═CH—CH═  (b-2);—CH═N—C(R^(2a))═CH—CH═  (b-3);—N═CH—C(R^(2a))═N—CH═  (b-4);—N═CH—C(R^(2a))═CH—N═  (b-5);—CH═N—C(R^(2a))═N—CH═  (b-6);—N═N—C(R^(2a))═CH—CH═  (b-7);q is 0, 1, 2; or where possible q is 3 or 4;

-   R¹ is hydrogen, aryl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,    C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl;.-   R^(2a) is cyano, aminocarbonyl, mono- or di(methyl)aminocarbonyl,    C₁₋₆alkyl substituted with cyano, aminocarbonyl or mono- or    di(methyl)aminocarbonyl, C₂₋₆alkenyl substituted with cyano, or    C₂₋₆alkynyl substituted with cyano;-   each R² independently is hydroxy, halo, C₁₋₆alkyl optionally    substituted with cyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl    optionally substituted with one or more halogen atoms or cyano,    C₂₋₆alkynyl optionally substituted with one or more halogen atoms or    cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,    amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,    polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,    —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶,    —C(═NH)R⁶ or a radical of formula

wherein each A independently is N, CH or CR⁶;

-   -   B is NH, O, S or NR⁶;    -   p is 1 or 2; and    -   R⁶ is methyl, amino, mono- or dimethylamino or polyhalomethyl;

-   L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, whereby    each of said aliphatic group may be substituted with one or two    substituents independently selected from    -   C₃₋₇cycloalkyl,    -   indolyl or isoindolyl, each optionally substituted with one,        two, three or four substituents each independently selected from        halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl,        nitro, amino, polyhalomethyl, polyhalomethyloxy and        C₁₋₆alkylcarbonyl,    -   phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,        wherein each of said aromatic rings may optionally be        substituted with one, two, three, four or five substituents each        independently selected from the substituents defined in R²; or

-   L is —X—R³ wherein    -   R³ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,        wherein each of said aromatic rings may optionally be        substituted with one, two, three, four or five substituents each        independently selected from the substituents defined in R²; and    -   X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)—        or —S(═O)₂—;

-   Q represents hydrogen, C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl or —NR⁴R⁵;    and

-   R⁴ and R⁵ are each independently selected from hydrogen, hydroxy,    C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl,    C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- or di(C₁₋₁₂alkyl)amino,    mono- or di(C₁₋₁₂alkyl)aminocarbonyl wherein each of the    aforementioned C₁₋₁₂alkyl groups may optionally and each    individually be substituted with one or two substituents each    independently selected from hydroxy, C₁₋₆alkyloxy,    hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₄alkyloxycarbonyl, cyano, amino,    imino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,    polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)R⁶,    —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶, aryl and    Het; or

-   R⁴ and R⁵ taken together may form pyrrolidinyl, piperidinyl,    morpholinyl, azido or mono- or di(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene;

-   Y represents hydroxy, halo, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally    substituted with one or more halogen atoms, C₂₋₆alkynyl optionally    substituted with one or more halogen atoms, C₁₋₆alkyl substituted    with cyano or —C(═O)R⁶, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,    carboxyl, cyano, nitro, amino, mono- or di(C₁₋₆alkyl)amino,    polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,    —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶,    —NHC(═O)R⁶, —C(═NH)R⁶ or aryl;

-   aryl is phenyl or phenyl substituted with one, two, three, four or    five substituents each independently selected from halo, C₁₋₆alkyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl and    polyhaloC₁₋₆alkyloxy;    Het is an aliphatic or aromatic heterocyclic radical; said aliphatic    heterocyclic radical is selected from pyrrolidinyl, piperidinyl,    homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and    tetrahydrothienyl wherein each of said aliphatic heterocyclic    radical may optionally be substituted with an oxo group; and said    aromatic heterocyclic radical is selected from pyrrolyl, furanyl,    thienyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein    each of said aromatic heterocyclic radical may optionally be    substituted with hydroxy, Het is meant to include all the possible    isomeric forms of the heterocycles mentioned in the definition of    Het, for instance, pyrrolyl also includes 2H-pyrrolyl; the Het    radical may be attached to the remainder of the molecule of formula    (I-B) through any ring carbon or heteroatom as appropriate, thus,    for example, when the heterocycle is pyridinyl, it may be    2-pyridinyl, 3-pyridinyl or 4-pyridinyl.    or    -   an antiviral compound of formula

the N-oxides, the pharmaceutically acceptable addition salts, quaternaryamines and the stereochemically isomeric forms thereof, wherein-a¹=a²-a³=a⁴- represents a bivalent radical of formula—CH═CH—CH═CH—  (a-1);—N═CH—CH═CH—  (a-2);—N═CH—N═CH—  (a-3);—N═CH—CH═N—  (a-4);—N═N—CH═CH—  (a-5);n is 0, 1, 2, 3 or 4; and in case -a¹=a²-a³=a⁴- is (a-1), then n mayalso be 5;

-   R¹ is hydrogen, aryl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,    C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl; and-   each R² independently is hydroxy, halo, C₁₋₆alkyl optionally    substituted with cyano or —C(═O)R⁴, C₃₋₇cycloalkyl, C₂₋₆alkenyl    optionally substituted with one or more halogen atoms or cyano,    C₂₋₆alkynyl optionally substituted with one or more halogen atoms or    cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,    amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,    polyhalomethyloxy, polyhalomethylthio,    -   —S(═O)_(p)R⁴, —NH—S(═O), —C(═O)R⁴, —NHC(═O)H, —C(═O)NHNH₂,        —NHC(═O)R⁴, —C(═NH)R⁴ or a radical of formula

wherein each A independently is N, CH or CR⁴;

-   -   B is NH, O, S or NR⁴;    -   p is 1 or 2; and    -   R⁴ is methyl, amino, mono- or dimethylamino or polyhalomethyl;

-   L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, whereby    each of said aliphatic group may be substituted with one or two    substituents independently selected from    -   C₃₋₇cycloalkyl,    -   indolyl or isoindolyl, each optionally substituted with one,        two, three or four substituents each independently selected from        halo, C₁₋₄alkyl, hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl,        nitro, amino, polyhalomethyl, polyhalomethyloxy and        C₁₋₆alkylcarbonyl,    -   phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,        wherein each of said aromatic rings may optionally be        substituted with one, two, three, four or five substituents each        independently selected from the substituents defined in R²; or        L is —X—R³ wherein

-   R³ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,    wherein each of said aromatic rings may optionally be substituted    with one, two, three, four or five substituents each independently    selected from the substituents defined in R²; and

-   X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O), —CHOH—, —S—, —S(═O)— or    —S(═O)₂—;

-   aryl is phenyl or phenyl substituted with one, two, three, four or    five substituents each independently selected from halo, C₁₋₆alkyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl and    polyhaloC₁₋₆alkyloxy;    with the proviso that compounds wherein    -   L is C₁₋₃alkyl; R¹ is selected from hydrogen, ethyl and methyl;        -a¹=a²-a³=a⁴- represents a bivalent radical of formula (a-1); n        is 0 or 1 and R² is selected from fluoro, chloro, methyl,        trifluoromethyl, ethyloxy and nitro; or    -   L is —X—R³, X is —NH—; R¹ is hydrogen; -a¹=a²-a³=a⁴- represents        a bivalent radical of formula (a-1); n is 0 or 1 and R² is        selected from chloro, methyl, methyloxy, cyano, amino and nitro        and R³ is phenyl, optionally substituted with one substituent        selected from chloro, methyl, methyloxy, cyano, amino and nitro;        and the compounds    -   N,N′-dipyridinyl-1,3,5)triazine-2,4-diamine;    -   (4-chloro-phenyl)-(4(1-4-isobutyl-phenyl)-ethyl)-(1,3,5)        triazin-2-yl)-amine are not included;        and        (b) one or more pharmaceutically acceptable water-soluble        polymers.

As used in the foregoing definitions and hereinafter halo definesfluoro, chloro, bromo and iodo; polyhalomethyl as a group or part of agroup is defined as mono- or polyhalosubstituted methyl, in particularmethyl with one or more fluoro atoms, for example, difluoromethyl ortrifluoromethyl; polyhaloC₁₋₆alkyl as a group or part of a group isdefined as mono- or polyhalosubstituted C₁₋₆alkyl, for example, thegroups defined in halomethyl, 1,1-difluoro-ethyl and the like; in casemore than one halogen atoms are attached to an alkyl group within thedefinition of polyhalomethyl or polyhaloC₁₋₆alkyl, they may be the sameor different; C₁₋₄alkyl as a group or part of a group encompasses thestraight and branched chained saturated hydrocarbon radicals having from1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyland the like; C₁₋₆-alkyl as a group or part of a group encompasses thestraight and branched chained saturated hydrocarbon radicals as definedin C₁₋₄alkyl as well as the higher homologues thereof containing 5 or 6carbon atoms such as, for example pentyl or hexyl; C₁₋₁₀alkyl as a groupor part of a group encompasses the straight and branched chainedsaturated hydrocarbon radicals as defined in C₁₋₆alkyl as well as thehigher homologues thereof containing 7 to 10 carbon atoms such as, forexample, heptyl, octyl, nonyl or decyl; C₁₋₁₂alkyl as a group or part ofa group encompasses the straight and branched chained saturatedhydrocarbon radicals as defined in C₁₋₁₀alkyl as well as the higherhomologues thereof containing 11 or 12 carbon atoms such as, forexample, undecyl, dodecyl and the like; C₁₋₄alkylidene as a group orpart of a group defines bivalent straight and branched chainedhydrocarbons having from 1 to 4 carbon atoms such as, for example,methylene, ethylidene, propylidene, butylidene and the like;C₁₋₄alkanediyl as a group or part of a group encompasses those radicalsdefined under C₁₋₄alkylidene as well as other bivalent straight andbranched chained hydro-carbons having from 1 to 4 carbon atoms such as,for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and thelike; C₃₋₇cycloalkyl as a group or part of a group is generic tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;C₃₋₁₀alkenyl as a group or part of a group defines straight and branchchained hydrocarbon radicals containing one double bond and having from3 to 10 carbon atoms such as, for example, 2-propenyl, 2-butenyl,2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 3-heptenyl,2-octenyl, 2-nonenyl, 2-decenyl and the like, whereby the carbon atomattached to the pyrimidine ring is preferably an aliphatic carbon atom;C₃₋₁₀alkynyl as a group or part of a group defines straight and branchchained hydrocarbon radicals containing one triple bond and having from3 to 10 carbon atoms such as, for example, 2-propenyl, 2-butynyl,2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 3-heptynyl,2-octynyl, 2-nonynyl, 2-decynyl and the like, whereby the carbon atomattached to the pyrimidine ring is preferably an aliphatic carbon atom;C₂₋₆alkenyl defines straight and branched chain hydrocarbon radicalshaving from 2 to 6 carbon atoms containing a double bond such asethenyl, propenyl, butenyl, pentenyl, hexenyl and the like; C₂₋₁₀alkenyldefines straight and branched chain hydrocarbon radicals having from 2to 10 carbon atoms containing a double bond such as the groups definedfor C₂₋₆alkenyl and heptenyl, octenyl, nonenyl, decenyl and the like;C₂₋₆alkynyl defines straight and branched chain hydrocarbon radicalshaving from 2 to 6 carbon atoms containing a triple bond such asethynyl, propynyl, butynyl, pentynyl, hexynyl and the like; C₂₋₁₀alkynyldefines straight and branched chain hydrocarbon radicals having from 2to 10 carbon atoms containing a triple bond such as the groups definedfor C₂₋₆alkynyl and heptynyl, octynyl, nonynyl, decynyl and the like;C₁₋₃alkyl as a group or part of a group encompasses the straight andbranched chain saturated hydrocarbon radicals having from 1 to 3 carbonatoms such as, methyl, ethyl and propyl; C₄₋₁₀alkyl encompasses thestraight and branched chain saturated hydrocarbon radicals as definedabove, having from 4 to 10 carbon atoms. The term C₁₋₆alkyloxy definesstraight or branched chain saturated hydrocarbon radicals such asmethoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy,1-methylethyloxy, 2-methyl-propyloxy, 2-methylbutyloxy and the like;C₃₋₆cycloalkyloxy is generic to cyclopropyloxy, cyclobutyloxy,cyclopentyloxy and cyclohexyloxy.

As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide group when attached once to asulfur atom, and a sulfonyl group when attached twice to a sulfur atom.

When any variable (e.g. aryl, R³, R⁴ in formula (I-A) etc.) occurs morethan one time in any constituent, each definition is independent.

Lines drawn into ring systems from substituents indicate that the bondmay be attached to any of the suitable ring atoms. For instance forcompounds of formula (I-A), R⁴ can be attached to any available carbonatom of the phenyl or pyridyl ring.

The addition salts as mentioned herein are meant to comprise thetherapeutically active addition salt forms which the compounds offormula (I-A), (I-B) or (I-C) are able to form with appropriate acids,such as, for example, inorganic acids such as hydrohalic acids, e.g.hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and thelike acids; or organic acids such as, for example, acetic, propanoic,hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic,fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare also meant to comprise the therapeutically active non-toxic base, inparticular, a metal or amine addition salt forms which the compounds ofthe present invention are able to form. Said salts can conveniently beobtained by treating the compounds of the present invention containingacidic hydrogen atoms with appropriate organic and inorganic bases suchas, for example, the ammonium salts, the alkali and earth alkaline metalsalts, e.g. the lithium, sodium, potassium, magnesium, calcium salts andthe like, salts with organic bases, e.g. the benzathine,N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids suchas, for example, arginine, lysine and the like. Conversely said saltforms can be converted by treatment with an appropriate base or acidinto the free acid or base form.

The term addition salts also comprises the hydrates and the solventaddition forms which the compounds of formula (I-A), (I-B) or (I-C) areable to form. Examples of such forms are e.g. hydrates, alcoholates andthe like.

The term stereochemically isomeric forms of the compounds of formula(I-A), (I-B) or (I-C), as used hereinbefore, defines all possiblecompounds made up of the same atoms bonded by the same sequence of bondsbut having different three-dimensional structures which are notinterchangeable, which the compounds of the present invention maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of a compound encompasses the mixture of all possiblestereochemically isomeric forms which said compound may possess. Saidmixture may contain all diastereomers and/or enantiomers of the basicmolecular structure of said compound. All stereochemically isomericforms of the compounds of formula (I-A), (I-B) or (I-C) both in pureform or in admixture with each other are intended to be embraced withinthe scope of the present invention.

Some of the compounds of formula (I-A), (I-B) or (I-C) may also exist intheir tautomeric forms. Such forms although not explicitly indicated inthe above formula are intended to be included within the scope of thepresent invention.

Whenever used hereinafter, the term compound of formula (I-A), (I-B) or(I-C) is meant to include any subgroup thereof, also the N-oxides, thepharmaceutically acceptable addition salts, the quaternary amines andall stereoisomeric forms.

Suitable compounds of formula (I-A) are those wherein Y is CR⁵ or N; Ais CH, CR⁴ or N; n is 0, 1, 2, 3 or 4; Q is —NR¹R²; R¹ and R² are eachindependently selected from hydrogen, hydroxy, C₁₋₁₂alkyl,C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl, C₁₋₁₂alkyloxy-carbonyl, aryl, amino,mono- or di(C₁₋₁₂alkyl)amino, mono- or di(C₁₋₁₂alkyl)amino-carbonylwherein each of the aforementioned C₁₋₁₂alkyl groups may optionally andeach individually be substituted with one or two substituents eachindependently selected from hydroxy, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,carboxyl, C₁₋₆alkyloxy-carbonyl, cyano, amino, imino, aminocarbonyl,aminocarbonylamino, mono- or di(C₁₋₆alkyl)amino, aryl and Het; or R¹ andR² taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azidoor mono- or di(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene; R³ is hydrogen, aryl,C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylsubstituted with C₁₋₆alkyloxycarbonyl; each R⁴ independently is hydroxy,halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl, trihalo-methyloxy; R⁵ is hydrogen or C₁₋₄alkyl; L is—X¹—R⁶ or —X²-Alk-R⁷ wherein R⁶ and R⁷ each independently are phenyl orphenyl substituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl, cyano, nitro, amino,and trifluoromethyl, X¹ and X² are each independently —NR³—, —NH—NH—,—N═N—, —O—, —S—, —S(═O)— or —S(═O)₂—, and Alk is C₁₋₄alkanediyl; aryl isphenyl or phenyl substituted with one, two, three, four or fivesubstituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, nitro and trifluoromethyl; Het is an aliphatic oraromatic heterocyclic radical; said aliphatic heterocyclic radical isselected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl,morpholinyl, tetrahydrofuranyl and tetrahydrothienyl wherein each ofsaid aliphatic heterocyclic radical may optionally be substituted withan oxo group; and said aromatic heterocyclic radical is selected frompyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl andpyridazinyl wherein each of said aromatic heterocyclic radical mayoptionally be substituted with hydroxy.

Most preferred compounds of formula (I-A) are

-   4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]benzonitrile    (*1.B1; comp. 1);-   6-[(2,6-dichlorophenyl)methyl]-N2-4-fluorophenyl)-2,4-pyrimidinediamine    (*1.B1; comp. 2);-   4-[[4-[(2,4-chlorophenyl)methyl]-6-[(4-hydroxybutyl)amino]-2-pyrimidinyl]amino]-benzonitrile    (*1.B2; comp. 3);-   4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(3-hydroxypropyl)amino]-2-pyrimidinyl]-amino]benzonitrile    (*1.B1; comp. 4);-   N-[2-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-4-pyrimidinyl]acetamide    (*1.B7; comp. 5);-   N-[2-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-4-pyrimidinyl]-butanamide    (*1.B7; comp. 6);-   4-[[2-amino-6-(2,6-dichlorophenoxy)-4-pyrimidinyl]amino]benzonitrile    (*1.B1; comp. 7);-   4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(2-hydroxy-2-phenylethyl)amino]-2-pyrimidinyl]amino]benzonitrile    (*1.B2; comp. 8);-   4-[[4-[(2,6-dichlorophenyl)methyl]6-[[3-(2-oxo-1-pyrrolidinyl)propyl]amino]-2-pyrimidinyl]amino]benzonitrile    (*1.B2; comp. 9);-   4-[[4-[(2,6-chlorophenyl)methyl]6-[[2-(2-hydroxyethoxy)ethyl]amino]-2-pyrimidinyl]amino]benzonitrile    monohydrochloride (*1.B2; comp. 10);-   4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(2,3-dihydroxypropyl)amino]-2-pyrimidinyl]-amino]benzonitrile    (*1B2; comp. 11);-   4-[[4-[(2,6-dichlorophenyl)methyl]-6-(hydroxyamino)-2-pyrimidinyl]amino]-benzonitrile    (*1.B4; comp. 12);-   4-[[4-[(2-cyanoethyl)amino]-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]-benzonitrile    (*1.B3; comp. 13);-   4-[[4-[(2,6-dichlorophenyl)methyl]-6-[[2-(1-pyrrolidinyl)ethyl]amino]-2-pyrimidinyl]-amino]benzonitrile    (*1.B3; comp. 14);-   4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-5-methyl-2-pyrimidinyl]amino]-benzonitrile    (*1.B1; comp. 15);-   N2-(4-bromophenyl)-6-[(2,6-dichlorophenyl)methyl]-5-methyl-2,4-pyrimidinediamine    (*1.B1; comp. 16);-   4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile    (*1.B8a; comp. 17);-   4-[[2-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinyl]amino]benzonitrile    (*1.B9a; comp. 18);-   4-[[4-[(2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile    (*1.B9a; comp. 19);-   4-[[4-[(2,4,6-trimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile    (*1.B10; comp. 20);-   4-[[⁴-[(2,6-dichlorophenyl)thio]-2-pyrimidinyl]amino]benzonitrile    (*1.B10; comp. 21);-   4-[[4-[[2,6-dibromo-4-(1-methylethyl)phenyl]amino]-2-pyrimidinyl]amino]benzonitrile    (*1.B9a; comp. 22);-   4-[[4-[[2,6-dichloro-4-(trifluoromethyl)phenyl]amino]-2-pyrimidinyl]amino]-benzonitrile    (*1.B9c; comp. 23);-   4-[[4-[(2,4-dichloro-6-methylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile    (*1.B9a; comp. 24);-   4-[[²-[(cyanophenyl)amino]-4-pyrimidinyl]amino]-3,5-methylbenzonitrile    (*1.B8a or 1.B8b; comp. 25);-   4-[[4-[(2,4-dibromo-6-fluorophenyl)amino]-2-pyrimidinyl]amino]benzonitrile    (*1.B9c; comp. 26);-   4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-5-methyl-2-pyrimidinyl]amino]-benzeneacetonitrile    (*1.B1; comp. 27);-   4-[[4-[methyl(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile    (*1.B9c; comp. 28);-   4-[[4-[(2,4,6-trichlorophenyl)amino]-2-pyrimidinyl]amino]benzonitrile    (*1.B9c; comp. 29);-   4-[[4-[(2,4,6-trimethylphenyl)thio]-2-pyrimidinyl]amino]benzonitrile    (*1.B10; comp. 30);-   4-[[4-[(2,4,6-trimethylphenyl)amino-2-pyrimidinyl]amino]benzonitrile    (*1.B11; comp. 31);-   4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile    (*1.B1; comp. 32);-   4-[[2-amino-6-[(2,4,6-trimethylphenyl)amino]4-pyrimidinyl]amino]benzonitrile    (*1.B1; comp. 33);-   4-(2-bromo-4-chloro-6-methylphenoxy)-2-pyrimidinyl]amino]benzonitrile    (*1.B10; comp. 34);-   4-[[4-[(4-chloro-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile    (*1.B9c; comp. 35);-   3,5-dichloro-4-[[2-[(4-cyanophenyl)amino]-4-pyrimidinyl]amino]benzonitrile    (*1.B9a; comp. 36);-   4-[[4-[[2,6-dichloro-4-(trifluoromethoxy)phenyl]amino]-2-pyrimidinyl]amino]-benzonitrile    (*1.B9c; comp. 37);-   4-[[4-[(2,4-dibromo-3,6-dichlorophenyl)amino]-2-pyrimidinyl]amino]benzonitrile    (*1.B9c; comp. 38);-   4-[[4-[(2,6-dibromo-4-propylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile    (*1.B9c; comp. 39);-   4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide    (*1.B11; comp. 40);-   4-[[4-[(4-(1,1-dimethylethyl)-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]-benzonitrile    (*1.B9a; comp. 41);-   4-[[2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile    (*1.B10; comp. 42);-   4-[[4-[(4-chloro-2,6-dimethylphenyl)amino]-5-methyl-2-pyrimidinyl]amino]-benzonitrile    (*1.B9c; comp. 43);-   4-[[2-[(4-cyanophenyl)amino]-5-methyl-4-pyrimidinyl]amino-3,5-dimethylbenzonitrile    (*1.B9b; comp. 44);-   4-[[4-[[4-(1,1-dimethylethyl)-2,6-dimethylphenyl]amino]-5-methyl-2-pyrimidinyl]-amino]benzonitrile    (*1.B9c; comp. 45);    4-[[4-[(4-bromo-2,6-dimethylphenyl)amino]-5-methyl-2-pyrimidinyl]amino]-benzonitrile    (*1.B9c; comp. 46);-   4-[[5-methyl-4-[(2,4,6-trimethylphenyl)thio]-2-pyrimidinyl]amino]benzonitrile    (*1.B9c; comp. 47);-   4-[[4-[(2,6-dibromo-4-propylphenyl)amino]-5-methyl-2-pyrimidinyl]amino]-benzonitrile    (*1.B9a; comp. 48);-   4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide,    N3-oxide (*1.B12; comp. 49);-   N2-(4-chlorophenyl)-N4-(2,4,6-trimethylphenyl)-2,4-pyrimidinediamine    (*1.B8a; comp. 50);-   4-[[4-[[2,6-dibromo-4-(1-methylethyl)phenyl]amino]-5-methyl-2-pyrimidinyl]amino]-benzonitrile    (*1.B9a; comp. 51);-   4-[[2-[(4-cyanophenyl)amino]-5-methyl-4-pyrimidinyl]amino]-3,5-dimethyl    Benzonitrile (*1.B9b; comp. 52);-   4-[[4-[(phenylmethyl)amino]-2-pyrimidinyl]amino]benzonitrile (comp.    53);-   4-[[4-amino-6-(2,6-dimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile    (*1.B15; comp. 54);-   4-[[4-amino-6-[(2-chloro-6-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile    (*1.B13a; comp. 55);-   4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile    (*1.B13a or 1.B13b; comp. 56);-   4-[[4-(hydroxyamino)-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile    (*1.B14; comp. 57);-   4-[[4-amino-6-[(2-ethyl-6-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile    (*1.B13b; comp. 58);-   4-[[4-amino-6-[(2,6-dichlorophenyl)thio]-1,3,5-triazin-2-yl]amino]benzonitrile    (*1.B13b; comp. 59);-   4-[[4-(hydroxyamino)-6-[(2,4,6-trichlorophenyl)amino-1,3,5-triazin-2-yl]amino]-benzonitrile    (*1.B14; comp. 60);-   4-[[4-amino-6-[(2,4,6-trimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile    (*1.B13b; comp. 61);-   4-[[4-(hydroxyamino)-6-(2,4,6-trimethylphenoxy)-1,3,5-triazin-2-yl]amino]-benzonitrile    (*1.B14; comp. 62);-   4-[[4-amino-6-[(2,4-dichloro-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile    (*1.B13b; comp. 63);-   4-[[4-[(2,4-dichloro-methylphenyl)amino]-6-(hydroxyamino)-1,3,5-triazin-2-yl]-amino]benzonitrile    (*1.B14; comp. 64);-   4-[[4-(hydroxyamino)-6-(2,4,6-trichlorophenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile    trifluoroacetate (1:1) (*1.B14; comp. 65);-   4-[[4-(4-acetyl-2,6-dimethylphenoxy)-6-amino-1,3,5-triazin-2-yl]amino]benzonitrile    (*1.B16; comp. 66);-   4-[[4-amino-6-(2,4,6-tribromophenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile    (*1.B17; comp. 67);-   4-[[4-amino-6-(4-nitro-2,6-dimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile    (*1.B17; comp. 68);-   4-[[4-amino-6-(2,6-dibromo-4-methylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile    (*1.B17; comp. 69);-   4-[[4-amino-6-(4-formyl-2,6-dimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile    (*1.B17; comp. 70);-   4-[[4-amino-[(2,4-dichlorophenyl)thio]-1,3,5-triazin-2-yl]amino]benzonitrile    (*1.B17; comp. 71);-   4-[[4-[(5-acetyl-2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-6-amino-1,3,5-triazin-2-yl]-amino]benzonitrile    (*1.B20; comp. 72);-   4-[[4-amino-6-[(4-bromo-2-chloro-6-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile    (*1.B20; comp. 73);-   4-[[4-amino-6-[(2-chloro-4,6-dimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile    (*1.B20; comp. 74);-   4-[[4-amino-6-[[2,4-dichloro-6-(trifluoromethyl)phenyl]amino]-1,3,5-triazin-2-yl]-amino]benzonitrile    (*1.B13; comp. 75);-   4-[[4-amino-6-[methyl(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile    (*1.B18; comp. 76);-   4-[[4-amino-6-[(2,6-dibromo-4-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile    (*1.B13b; comp. 77);-   4-[[4-amino-[[2,6-dibromo-4-(1-methylethyl)phenyl]amino]-1,3,5-triazin-2-yl]-amino]benzonitrile    (*1.B13b; comp. 78);    the N-oxides, the pharmaceutically acceptable addition salts and the    stereochemically isomeric forms thereof (* indicates the example    number of the preparation procedure listed in the experimental part    according to which the compound of formula (I-A) was synthesized).

Suitable compounds of formula (I-B) are those wherein one or more of thefollowing restrictions apply:

-   i) -b¹=b²-C—(R^(2a))=b³-b⁴= is a radical of formula (b-1);-   ii) q is 0;-   iii) R^(2a) is cyano or —C(═O)NH₂, preferably R^(2a) is cyano;-   iv) Y is cyano, —C(═O)NH₂ or a halogen, preferably a halogen;-   v) Q is hydrogen or —NR⁴R⁵ wherein R⁴ and R⁵ are preferably    hydrogen;-   vi) L is —X—R³ wherein X is preferably NR¹, O or S, most preferably    X is NH, and R³ is substituted phenyl with C₁₋₆alkyl, halogen and    cyano as preferred substituents.

Another interesting group of compounds of formula (I-B) are thosecompounds of formula (I-B) wherein L is —X—R³ wherein R³ is2,4,6-trisubstituted phenyl, each substituent independently selectedfrom chloro, bromo, fluoro, cyano or C₁₋₄alkyl.

Also interesting are those compounds of formula (I-B) wherein Y ischloro or bromo and Q is hydrogen or amino.

Particular compounds of formula (I-B) are those compounds of formula(I-B) wherein the moiety in the 2 position of the pyrimidine ring is a4-cyano-anilino group.

Preferred compounds of formula (I-B) are those compounds of formula(I-B) wherein the moiety in the 2 position of the pyrimidine ring is a4-cyano-anilino group, L is —X—R³ wherein R³ is a 2,4,6-trisubstitutedphenyl, Y is a halogen and Q is hydrogen or NH₂.

Most preferred compounds of formula (I-B) are:

-   4-[[4-amino-5-chloro-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]-benzonitrile;-   4-[[5-chloro-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-amino-5-chloro-6-[(4-cyano-2,6-methylphenyl)amino]-2-pyrimidinyl]amino]-benzonitrile;-   4-[[5-bromo-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-amino-5-chloro-6-(4-cyano-2,6-methylphenyloxy)-2-pyrimidinyl]amino]-benzonitrile;    and-   4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]-benzonitrile;    the N-oxides, the pharmaceutically acceptable addition salts,    quaternary amines and the stereocherically isomeric forms thereof.

An interesting group of compounds of formula (I-C) are those compoundsof formula (I-C) wherein one or more of the following conditions aremet:

-   (i) n is 1;-   (ii) -a¹=a²-a³=a⁴- represents a bivalent radical of formula (a-1);-   (iii) R¹ is hydrogen or alkyl;-   (iv) R² is cyano; aminocarbonyl; mono- or di(methyl)aminocarbonyl;    C₁₋₄alkyl substituted with cyano, aminocarbonyl or mono- or    di(methyl)aminocarbonyl; and more in particular, R² is on the 4    position relative to the —NR¹— moiety;-   i) L is —X—R³ wherein X is preferably —NR¹—, —O—, —S—, most    preferably X is —NH—, and R³ is substituted phenyl with C₁₋₆alkyl,    halogen and cyano as preferred substituents.

Preferred compounds of formula (I-C) are those compounds of formula(I-C) wherein L is —X—R³ wherein R³ is a disubstituted phenyl group or atrisubstituted phenyl group, each substituent independently selectedfrom chloro, bromo, fluoro, cyano or C₁₋₄alkyl.

Most preferred compound of formula (I-C) is4-[[4-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile.

The compounds of formula (I-A) can be prepared according to art-knownprocedures.

In particular, the compounds of formula (I-A) can generally be preparedby reacting an intermediate of formula (II), wherein W¹ is a suitableleaving group such as, for example, a halo atom with an amino derivativeof formula (III) in a reaction inert solvent such as, for example,1,4-dioxane, tetrahydrofuran, 2-propanol, N-methyl-pyrrolidinone and thelike, optionally in the presence of a suitable base such as, forexample, sodiumhydroxide, sodiumhydride, triethylamine orN,N-di-isopropyl-ethylamine or the like.

In case Q is NR¹R² and R² contains a hydroxy moiety, it may beconvenient to perform the above reaction with a protected form ofintermediate (III) whereby the hydroxy moiety bears a suitableprotecting group P being, for instance, a benzyl, and subsequentlyremoving the protective group according to art-known methodologies, suchas, for example, reacting with BBr₃ in dichloromethane under nitrogenatmosphere.

Compounds of formula (I-A) wherein Y is CR⁵, said compounds beingrepresented by formula (I-A-a), may also be prepared by reacting anintermediate of formula (IV) wherein W¹ is a suitable leaving group suchas, for example, a halo atom, with an amino derivative of formula (V),optionally in a solvent such as, for example, water, 2-propanol,diethylether, 1-methyl-2-pyrrolidinone and the like, and optionally inthe presence of an acid such as, for example, 1 N hydrochloric acid indiethylether. It may be convenient to perform the reaction under areaction-inert atmosphere such as, for example, oxygen free argon ornitrogen.

Compounds of formula (I-A-a) wherein L is —X¹—R⁶, said compounds beingrepresented by formula (I-A-a-1), can also be prepared by reacting anintermediate of formula (VI) with an intermediate of formula (VII) in asuitable solvent such as, for example, 1,4-dioxane.

Depending on the nature of X¹ a suitable base or acid may be used toimprove the reaction rate. For instance, in case X¹ is —O—, sodiumhydride may be used as suitable base; or in case X¹ is —NR³—, HCl may beused as a suitable acid.

The compounds of formula (I-A), wherein Y is N, said compounds beingrepresented by formula (I-A-b), can also conveniently be prepared usingsolid phase synthesis techniques. In general, solid phase synthesisinvolves reacting an intermediate in a synthesis with a polymer support.This polymer supported intermediate can then be carried on through anumber of synthetic steps. After each step, impurities are removed byfiltering the resin and washing it numerous times with various solvents.At each step the resin can be split up to react with variousintermediates in the next step thus allowing for the synthesis of alarge number of compounds. After the last step in the procedure theresin is treated with a reagent or process to cleave the resin from thesample.

Suitable polymer supports include for instance Rink Amide resin(Calbiochem-Novabiochem Corp., San Diego, Calif.).

For instance, the compounds of formula (I-A-b) wherein n is 1 and the R⁴substituent is placed in the meta position of A, and NR¹R² is NH₂, saidcompounds being represented by formula (I-A-b-1), were preparedaccording to the procedure depicted in Scheme 1.

In scheme 1, Rink Amide resin is reacted in a suitable solvent such as,for example N,N-dimethylformamide in the presence of piperidine toobtain the primary amine of formula (VIII-a) which can then further bereacted with an intermediate of formula (IX) wherein W¹ is a suitableleaving group such as, for example, a halo atom, in the presence of abase such as for example, N,N-diisopropylethylaamine, in a suitablesolvent such as, for example, dimethylsulfoxide. Impurities can beremoved by washing numerous times with various solvents such as, forexample, N,N-dimethylformamide, dichloromethane, dimethylsulfoxide andthe like. The resulting polymer-bound intermediate of formula (VIII-b)was then further reacted with L—H (X). To facilitate thistransformation, silver triflate, sodium hexamethyldisilazide or cesiumcarbonate may be used. The resin is finally treated with a cleavagereagent such as for example trifluoroacetic acid in tetrahydrofuran,thus obtaining compounds of formula (I-A-b-1).

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, distillation, trituration andchromatography.

The compounds of formula (I-A) may further be prepared by convertingcompounds of formula (I-A) into each other according to art-known grouptransformation reactions.

The compounds of formula (I-A) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I-A) withan appropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.t.butyl hydro-peroxide. Suitable solvents are, for example, water, loweralcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

For instance, compounds of formula (I-A-a) wherein Q is NR¹R² and R¹ andR² are taken together to form mono- ordi(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene, said compounds being represented byformula (I-A-a-2), may be prepared by reacting a compound of formula(I-A-a) wherein R¹ and R² are hydrogen, said compound being representedby formula (I-A-a-3), with an intermediate of formula (XI) or afunctional derivative thereof.

Also, compounds of formula (I-A-a) wherein Q is NR¹R² and R¹ and R² arehydrogen may further be reacted with an acyl halide or an alkylchloroformate in a reaction-inert solvent such as, for exampledichloromethane, in the presence of a suitable base, such as, forexample, pyridine, to form die corresponding amide, respectively,carbamate derivative.

Some of the compounds of formula (I-A) and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I-A) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Some of the intermediates and starting materials are known compounds andmay be commercially available or may be prepared according to art-knownprocedures.

Intermediates of formula (II), wherein Y is CR⁵, said intermediatesbeing represented by formula (II-a), can be prepared by reacting anintermediate of formula (XII) with an intermediate of formula (V)analogously to the preparation of compounds of formula (I-a).

A particular subgroup of the intermediates of formula (II-a) isrepresented by formula

wherein n is 0, 1, 2, or 3.

Particular intermediates of formula (II′-a) are those wherein W¹ is ahalo atom, more in particular, a chloro atom.

Intermediates of formula (II), wherein Y is N, R⁴ is placed inparaposition of NR³, and n is 1, said intermediates being represented byformula (II-b-1) can be prepared by reacting an intermediate of formula(XIII) wherein W¹ is a suitable leaving group such as, for example, ahalogen, with an amine derivative of formula (XIV) in a reaction-inertsolvent such as, for example, tetrahydrofuran, 1,4-dioxane or the like,in the presence of a suitable base such as, for example, triethylamine;and subsequently reacting the thus obtained intermediate of formula (XV)with an intermediate of formula (XVI) in a reaction-inert solvent suchas, for example, acetonitrile, 1,4-dioxane or the like, in the presenceof a base such as, for example, potassium carbonate, sodium hydride,N,N-diisopropyl-ethylamine or the like.

The order of the above reaction scheme may also be reversed, i.e. firstan intermediate of formula (XIII) may be reacted with an intermediate offormula (XVI), and then, the resulting intermediate of formula (XVII)may further be reacted with an amine derivative of formula (XIV); thusforming an intermediate of formula (II-b-1).

Particular intermediates are those intermediates of formula (II-1)wherein R⁴ is cyano, amino, carbonyl, nitro or trifluoromethyl, R³ ishydrogen, A is CH, W¹ is a halogen such as, chloro and bromo, and L isas defined in the compounds of formula (I) provided that R⁶ is otherthan p-cyano-phenyl, p-nitro-phenyl, p-methoxy-phenyl andp-aminocarbonyl-phenyl, and R⁷ is other than2-(4-hydroxyphenyl)ethyl]amino; more in particular, R³, A and W¹ are asdefined above, R⁴ is cyano and L is —X¹—R⁶ or X²-Alk-R⁷; wherein R⁶ andR⁷ each independently are indanyl, indolyl or phenyl; each of saidindanyl, indolyl or phenyl may be substituted with two, three, four orfive substituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy, hydroxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl,cyano, nitro, amino and trifluoromethyl.

Intermediates of formula (IV) wherein Q is NR¹R², said intermediatesbeing represented by formula (IV-a), can be prepared by reacting apyrimidine derivative of formula (XVIII) wherein W¹ is a suitableleaving group such as, for example, a halo atom, with an intermediate offormula (III) in a reaction inert solvent such as, for example,1,4-dioxane, 2-propanol or the like. Different regio-specific isomersmay be formed and can be separated from one another using suitableseparation techniques such as, for example, chromatography.

Intermediates of formula (XVIII) whereby L is L′—CH₂ and is attached inthe 2 position of the pyrimidine ring and W¹ is chloro, saidintermediates being represented by formula (XVIII-a), can be prepared byreacting an imidamide of formula (XIX) with a propanedioic acid ester offormula (XX) in a solvent such as, for example, ethanol, and in thepresence of, for instance, sodium, and subsequently reacting the thusformed intermediate of formula (XXI) with a suitable reagent such as,for example, phosphoryl chloride.

Intermediates of formula (XVIII) whereby L is L′—CH₂ and is attached inthe 4 or 6 position of the pyrimidine ring and W¹ is chloro, saidintermediates being represented by formula (XVIII-b), can be prepared byreacting an intermediate of formula (XXII) with urea or a functionalderivative thereof, in a solvent such as, for example, ethanol, and inthe presence of, for instance, sodium, and subsequently reacting thethus formed intermediate of formula (XXIII) with a suitable reagent suchas, for example, phosphoryl chloride.

Intermediates of formula (XVIII) wherein L is L′—CH₂ and is attachedanywhere on the pyrimidine ring, said intermediates being represented byformula (XVIII-c), can be prepared by reacting an intermediate offormula (XXIV), wherein W¹ is a suitable leaving group such as, forexample, a halo atom, with an intermediate of formula (XXV) wherein W²is a suitable leaving group such as, for example, a halogen, accordingto the procedure of a Grignard reaction.

Intermediates of formula (XVIII) wherein L is -Z—R⁶, -Z- representingtherein —O— or —NH—, and -Z—R⁶ is attached in the 4 or 6 position of thepyrimidine ring, said intermediates being represented by formula(XVIII-d), can be prepared by reacting an intermediate of formula (XXVI)with an intermediate of formula (XXVII) wherein W¹ is a suitable leavinggroup such as, for example, a halo atom, in a reaction-inert solventsuch as, for example, tetrahydrofuran or 1,4-dioxane, and in thepresence of a suitable base such as, for example, potassium hydroxide ordiisopropyl ethanamine, or sodium hydride.

Compounds of formula (I-A) and some of the intermediates may have one ormore stereogenic centers in their structure, present in a R or a Sconfiguration.

In general, compounds of formula (I-B) can be prepared by reacting anintermediate of formula (II(b)) wherein W¹ is a suitable leaving groupsuch as, for example, a halogen, hydroxy, triflate, tosylate,thiomethyl, methylsulfonyl, trifluoromethylsulfonyl and the like, withan amino derivative of formula (III(b)) optionally under solvent-freeconditions or in a reaction-inert solvent such as, for example, ethanol,1-methyl-2-pyrrolidinone, N,N-dimethylformamide, 1,4-oxane,tetrahydrofuran, dimethyl sulfoxide, tetraline, sulfolane, acetonitrileand the like, under a reaction-inert atmosphere such as, for example,oxygen free argon or nitrogen, and optionally in the presence of an acidsuch as, for example, 1 N hydrochloric acid in diethyl ether or thelike. This reaction can be performed at a temperature ranging between50° C. and 250° C.

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, distillation, trituration andchromatography.

The compounds of formula (I-B) wherein L is a radical of formula—NR¹—R³, said compounds being represented by formula (I-B-1), can beprepared by reacting an intermediate of formula (IV(b)) wherein W² is asuitable leaving group such as, for example, a halogen or a triflate,with an intermediate of formula (V(b)) under solvent-free conditions orin an appropriate solvent such as, for example, ethanol,1-methyl-2-pyrrolidinone, N,N-dimethylformamide, 1,4-dioxane,tetrahydrofuran, dimethyl sulfoxide, tetraline, sulfolane, acetonitrileand the like, under a reaction-inert atmosphere such as, for example,oxygen free argon or nitrogen, and optionally in the presence of an acidsuch as, for example, 1 N hydrochloric acid in diethyl ether. Thisreaction can be performed at a temperature ranging between 50° C. and250° C.

The compounds of formula (I-B) wherein L is a radical of formula —O—R³,said compounds being represented by formula (I-B-2), can be prepared byreacting an intermediate of formula (IV(b)) wherein W² is a suitableleaving group such as, for example a halogen or a triflate, with anintermediate of formula (VI(b)) in an appropriate solvent such as, forexample, 1,4-dioxane, dimethyl sulfoxide, tetraline, sulfolane and thelike under a reaction-inert atmosphere such as, for example, oxygen freeargon or nitrogen, and in the presence of a base such as, for example,sodium hydride, potassium hydride, sodium hydroxide or the like. Thisreaction can be performed at a temperature ranging between 50° C. and250° C.

The compounds of formula (I-B) may further be prepared by convertingcompounds of formula (I-B) into each other according to art-known grouptransformation reactions.

The compounds of formula (I-B) may be converted to the correspondingN-oxide forms by the procedures described hereinabove.

For instance, the compounds of formula (I-B) wherein Q is a halogen maybe converted to the corresponding compounds wherein Q is —NR⁴H usingNH₂R⁴ as a reagent in a reaction inert solvent such as, for example,1,4-dioxane and the like, optionally in the presence of a suitable basesuch as, for example, triethylamine or N,N-diisopropyl-ethylamine or thelike. In case R⁴ contains a hydroxy moiety, it may be convenient toperform the above reaction with a protected form of NH₂R⁴ whereby thehydroxy moiety bears a suitable protecting group P being, for instance,a trialkylsilyl group, and subsequently removing the protective groupaccording to art-known methodologies.

Some of the compounds of formula (I-B) and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I-B) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Some of the intermediates and starting materials are known compounds andmay be commercially available or may be prepared according to art-knownprocedures.

Intermediates of formula (II(b)) wherein L is —X—R³, said intermediatesbeing represented by formula (II(b)-1), can be prepared by reacting apyrimidine derivative of formula VII(b)) wherein each W¹ is as definedpreviously, with HXR³ (VIII(b)) in a reaction inert solvent such as, forexample, 1,4-dioxane, 2-propanol or the like, and in the presence of abase such as, for example, triethylamine or N,N-diisopropylethyl-amineor the like. Different regio-specific isomers may be formed and can beseparated from one another using suitable separation techniques such as,for example, chromatography.

Intermediates of formula (IV(b)) can be prepared by reacting anintermediate of formula (VII(b)-a) wherein W² is a suitable leavinggroup such as, for example, a halogen, with an intermediate of formula(IX(b)) in a suitable solvent such as, for example,1-methyl-2-pyrrolidinone, 1,4-dioxane or the like, in the presence of anacid such as, for example, 1 N hydrochloric acid in diethyl ether. Thisreaction can be performed at a temperature ranging between 50° C. and250° C.

Alternatively, intermediates of formula (IV(b)) can be prepared byreacting an intermediate of formula (X(b)) with phosphorous oxychloride,triflic anhydride or a functional derivative thereof under areaction-inert atmosphere such as, for example, oxygen free argon ornitrogen. This reaction can be performed at a temperature rangingbetween 20° C. and 150° C.

Intermediates of formula (X(b)) can be prepared by reacting anintermediate of formula (XI(b)) or a functional derivative thereof, withan intermediate of formula (IX(b)). This reaction may be performed undersolvent-free conditions or in an appropriate solvent such as, forexample, diglyme, tetraline or the like under a reaction-inertatmosphere such as, for example, oxygen free argon or nitrogen, andoptionally in the presence of a base such as, for example, sodiumhydride, potassium hydride or the like. This reaction can be performedat a temperature ranging between 100° C. and 250° C.

Intermediates of formula (X(b)) can also be prepared by reacting anintermediate of formula (XII(b)), wherein W² is a suitable leaving groupand Y and Q are defined as described for a compound of formula (I-B),with an intermediate of formula (XIII(b)) in an appropriate solvent suchas, for example, ethanol, or the like, and in the presence of a basesuch as, for example, sodium ethoxide or the like, under areaction-inert atmosphere such as, for example, oxygen free argon ornitrogen. The reaction can be performed at a temperature ranging between20° C. and 125° C.

A convenient way of preparing an intermediate of formula (IV(b)) whereinY is a bromine or chloro atom, said intermediates being represented byformula (IV(b)-1), involves the introduction of a bromine or chloro atomto an intermediate of formula (XIV(b)) using N-bromosuccinimide orN-chlorosuccinimide in a reaction-inert solvent such as, for example,chloroform, carbon tetrachloride or the like. This reaction can beperformed at a temperature ranging between 20° C. and 125° C.

Analogous to the conversion of compounds of formula (I-B) wherein Q is ahalogen to compounds of formula (I-B) wherein Q is —NHR⁴, theintermediates of formula (II(b)), (V(b)) and (VII(b)) can also beconverted.

Compounds of formula (I-C) wherein L is a radical of formula —X—R³, saidcompounds are represented by formula (I-C-a), can be prepared byreacting an intermediate of formula (II(c)) wherein W¹ is a suitableleaving group, for example, a halogen, with an amine derivative offormula (III(c)) in a reaction-inert solvent, for example,tetrahydrofuran, 1,4-dioxane or the like, in the presence of a suitablebase such as, triethylamine; and subsequently reacting the thus obtainedintermediate of formula (IV(c)) with an intermediate of formula (V(c))in a reaction-inert solvent such as acetonitrile, 1,4-dioxane or thelike, in the presence of a base such as potassium carbonate, sodiumhydride, N,N-diisopropyl-ethylamine or the like.

The order of the above reaction scheme may also be reversed, i.e. firstan intermediate of formula (II(c)) may be reacted with an intermediateof formula (V(c)), and then, the resulting intermediate may further bereacted with an amine derivative of formula (III(c)); thus forming acompound of formula (I-C-a).

The reaction products may be isolated from the reaction medium and, ifnecessary, further purified according to methodologies generally knownin the art such as, extraction, crystallization, distillation,trituration and chromatography.

Compounds of formula (I-C) wherein L is an optionally substitutedC₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, said compoundsare represented by formula (I-C-b), can be prepared by first making aGrignard reagent of an intermediate of formula (VI(c)) wherein W² is asuitable substituent such as, a halogen, e.g. bromine, in the presenceof magnesium in a reaction-inert solvent such as, diethyl ether, andsubsequently reacting said Grignard reagent with an intermediate offormula (II(c)) wherein W¹ is a suitable leaving group such as, ahalogen, e.g. chlorine, in a reaction-inert solvent, for example,benzene, thus forming an intermediate of formula (VII(c)). It may beconvenient to perform the above reaction under a inert atmosphere, forinstance, argon. Intermediate (VII(c)) may be isolated from its reactionmedium, or may be in situ further reacted with an intermediate offormula (III(c)) in a reaction-inert solvent such as, 1,4-dioxane, andin the presence of a suitable base such as, diisopropylethylamine or thelike, thus forming a compound of formula (I-C-b).

The compounds of formula (I-C) may further be prepared by convertingcompounds of formula (I-C) into each other according to art-known grouptransformation reactions.

The compounds of formula (I-C) may be converted to the correspondingN-oxides by the procedures as described hereinabove.

Some of the intermediates as mentioned hereinabove are commerciallyavailable or can be prepared according to art-known procedures.

Compounds of formula (I-C) and some of the intermediates may have one ormore stereogenic centers in their structure, present in a R or a Sconfiguration.

The compounds of formula (I-A), (I-B) or (I-C) as prepared in thehereinabove described processes may be synthesized as a mixture ofstereoisomeric forms, in particular in the form of racemic mixtures ofenantiomers which can be separated from one another following art-knownresolution procedures. The racemic compounds of formula (I-A), (I-B) or(I-C) may be converted into the corresponding diastereomeric salt formsby reaction with a suitable chiral acid. Said diastereomeric salt formsare subsequently separated, for example, by selective or fractionalcrystallization and the enantiomers are liberated therefrom by alkali.An alternative manner of separating the enantiomeric forms of thecompounds of formula (I-A), (I-B) or (I-C) involves liquidchromatography using a chiral stationary phase. Said purestereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

It will be appreciated by those skilled in the art that in the processesdescribed above the functional groups of intermediate compounds toprepare compounds of formula (I-A), (I-B) or (I-C) may need to beblocked by protecting groups.

Functional groups which it is desirable to protect include hydroxy,amino and carboxylic acid. Suitable protecting groups for hydroxyinclude trialkylsilyl groups (e.g. tert-butyldimethylsilyl,tert-butyldiphenylsilyl or trimethylsilyl), benzyl andtetrahydropyranyl. Suitable protecting groups for amino includetert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groupsfor carboxylic acid include C₁₋₆alkyl or benzyl esters.

The protection and deprotection of functional groups may take placebefore or after a reaction step.

The use of protecting groups is fully described in ‘Protective Groups inOrganic Chemistry’, edited by J W F McOmie, Plenum Press (1973), and‘Protective Groups in Organic Synthesis’ 2^(nd) edition, T W Greene & PG M Wutz, Wiley Interscience (1991).

The compounds of formula (I-A), (I-B) and (I-C) and the intermediates offormula (II′-a) unexpectedly show antiretroviral properties, inparticular against Human Immunodeficiency Virus (HIV), which is theaetiological agent of Acquired Immune Deficiency Syndrome (AIDS) inhumans. The HIV virus preferentially infects human T-4 cells anddestroys them or changes their normal function, particularly thecoordination of the immune system. As a result, an infected patient hasan everdecreasing number of T-4 cells, which moreover behave abnormally.Hence, the immunological defense system is unable to combat infectionsand neoplasms and the HIV infected subject usually dies by opportunisticinfections such as pneumonia, or by cancers. Other conditions associatedwith HIV infection include thrombocytopaenia, multiple sclerosis,Kaposi's sarcoma and infection of the central nervous systemcharacterized by progressive demyelination, resulting in dementia andsymptoms such as, progressive dysarthria, ataxia and disorientation. HIVinfection further has also been associated with peripheral neuropathy,progressive generalized lymphadenopathy (PGL) and AIDS-related complex(ARC).

The compounds of formula (I-A), (I-B) and (I-C) also show activityagainst HIV-1 strains that have acquired resistance to art-knownnon-nucleoside reverse transcriptase inhibitors. They also have littleor no binding affinity to human α-1 acid glycoprotein.

Those of skill in the treatment of HIV-infection could determine theeffective daily amount from the test results presented here. In generalit is contemplated that an effective daily amount would be from 0.01mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 1 to 1000 mg, in particular 5 to 600 mgof active ingredient per unit dosage form, and more in particular from200 to 400 mg per unit dosage form or from 5 to 200 mg of activeingredient per unit dosage form depending on the particular compoundbeing used.

The exact dosage and frequency of administration depends on theparticular compound of formula (I-A), (I-B) or (I-C) used, theparticular condition being treated, the severity of the condition beingtreated, the age, weight and general physical condition of theparticular patient as well as other medication the individual may betaking, as is well known to those skilled in the art. Furthermore, it isevident that said effective daily amount may be lowered or increaseddepending on the response of the treated subject and/or depending on theevaluation of the physician prescribing the compounds of the instantinvention. The effective daily amount ranges mentioned hereinabove aretherefore only guidelines and are not intended to limit the scope or useof the invention to any extent.

The compounds of formula (I-A), (I-B) or (I-C) can also be used in thepresent invention in combination with another compound of formula (I-A),(I-B) or (I-C) or with another antiretroviral compound. Thus, thepresent invention also relates to a pharmaceutical compositioncontaining (a) a compound of formula (I-A), (I-B) or (I-C), (b) anothercompound of formula (I-A), (I-B) or (I-C) or another antiretroviralcompound, and (c) one or more water-soluble polymers, as a combinedpreparation for anti-HIV treatment. Said other antiretroviral compoundsmay be known antiretroviral compounds such as nucleoside reversetranscriptase inhibitors, e.g. zidovudine (3′-azido-3′-deoxythymidine,AZT), didanosine (dideoxy inosine; ddI), zalcitabine (dideoxycytidine,ddC) or lamivudine (3′-thia-2′-3′-dideoxycytidine, 3TC) and the like;non-nucleoside reverse transciptase inhibitors such as suramine,foscamet-sodium (trisodium phosphono formate), nevirapine(11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one), sustiva (efavirenz), tacrine(tetrahydroaminoacridine) and the like; compounds of the TIBO(tetrahydro-imidazo-[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one andthione)-type e.g.(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;compounds of the α-APA (α-anilino phenyl acetamide) type e.g.α-[(2-nitro-phenyl)amino]-2,6-dichlorobenzene-acetamide and the like;TAT-inhibitors, e.g. RO-5-3335 and the like; protease inhibitors e.g.indinavir, ritanovir, saquinovir and the like; NMDA receptor inhibitorse.g. pentamidine; α-glycosidase inhibitor e.g. castanospermine and thelike; Rnase H inhibitor e.g. dextran (dextran sulfate) and the like; orimmunomodulating agents, e.g. levamisole, thymopentin and the like.

The term “a solid dispersion” defines a system in a solid state (asopposed to a liquid or gaseous state) comprising at least twocomponents, wherein one component is dispersed more or less evenlythroughout the other component or components. When said dispersion ofthe components is such that the system is chemically and physicallyuniform or homogenous throughout or consists of one phase as defined inthermo-dynamics, such a solid dispersion will be called “a solidsolution” hereinafter. Solid solutions are preferred physical systemsbecause the components therein are usually readily bioavailable to theorganisms to which they are administered. This advantage can probably beexplained by the ease with which said solid solutions can form liquidsolutions when contacted with a liquid medium such as gastric juice. Theease of dissolution may be attributed at least in part to the fact thatthe energy required for dissolution of the components from a solidsolution is less than that required for the dissolution of componentsfrom a crystalline or microcrystalline solid phase.

The term “a solid dispersion” also comprises dispersions which are lesshomogenous throughout than solid solutions. Such dispersions are notchemically and physically uniform throughout or comprise more than onephase. For example, the term “a solid dispersion” also relates toparticles having domains or small regions wherein amorphous,microcrystalline or crystalline (a), or amorphous, microcrystalline orcrystalline (b), or both, are dispersed more or less evenly in anotherphase comprising (b), or (a), or a solid solution comprising (a) and(b). Said domains are regions within the particles distinctively markedby some physical feature, small in size compared to the size of theparticle as a whole, and evenly and randomly distributed throughout theparticle.

As described hereinabove, the particles of the present invention alsocomprise one or more water-soluble polymers.

The water-soluble polymer in the particles according to the presentinvention is a polymer that preferably has an apparent viscosity, whendissolved at 20° C. in an aqueous solution at 2% (w/v), of 1 to 5000mPa·s more preferably of 1 to 700 mPa·s, and most preferred of 1 to 100mPa·s. For example, the water-soluble polymer can be selected from thegroup comprising

-   alkylcelluloses such as methylcellulose,-   hydroxyalkylcelluloses such as hydroxymethylcellulose,    hydroxyethylcellulose, hydroxypropylcellulose and    hydroxybutylcellulose,-   hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose    and hydroxypropyl methylcellulose,-   carboxyalkylcelluloses such as carboxymethylcellulose,-   alkali metal salts of carboxyalkylcelluloses such as sodium    carboxymethylcellulose,-   carboxyalkylalkylcelluloses such as carboxymethylethylcellulose,-   carboxyalkylcellulose esters,-   starches,-   pectines such as sodium carboxymethylamylopectine,-   chitin derivates such as chitosan,-   di-, oligo- and polysaccharides such as trehalose, cyclodextrins and    derivatives thereof, alginic acid, alkali metal and ammonium salts    thereof, carrageenans, galactomannans, tragacanth, agar-agar, gummi    arabicum, guar gummi and xanthan gummi,-   polyacrylic acids and the salts thereof,-   polymethacrylic acids, the salts and esters thereof, methacrylate    copolymers,-   polyvinylalcohol,-   polyalkylene oxides such as polyethylene oxide and polypropylene    oxide and copolymers of ethylene oxide and propylene oxide.

Preferred water-soluble polymers are Eudragit E® and hydroxypropylmethylcelluloses (HPMC).

Said Eudragit E® (Röhm GmbH, Germany) is an aminoalkyl methacrylatecopolymer, more in particular poly(butyl methacrylate,(2-dimethylaminoethyl)methacrylate, methyl methacrylate) (1:2:1). Thisbasic polymethacrylate is soluble in gastric fluid up to pH 5. EudragitE® 100, which is a solvent-free Eudragit E® solid substance ispreferred.

Said HPMC contains sufficient hydroxypropyl and methoxy groups to renderit water-soluble. HPMC having a methoxy degree of substitution fromabout 0.8 to about 2.5 and a hydroxypropyl molar substitution from about0.05 to about 3.0 are generally water-soluble. Methoxy degree ofsubstitution refers to the average number of methyl ether groups presentper anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molarsubstitution refers to the average number of moles of propylene oxidewhich have reacted with each anhydroglucose unit of the cellulosemolecule. Hydroxypropyl methylcellulose is the United States AdoptedName for hypromellose (see Martindale, The Extra Pharmacopoeia, 29thedition, page 1435). In the four digit number “2910”, the first twodigits represent the approximate percentage of methoxyl groups and thethird and fourth digits the approximate percentage composition ofhydroxypropoxyl groups; 5 mPa·s is a value indicative of the apparentviscosity of a 2% aqueous solution at 20° C.

The molecular weight of the HPMC normally affects both the releaseprofile of the milled extrudate as well as its physical properties. Adesired release profile can thus be designed by choosing an HPMC of anappropriate molecular weight; for immediate release of the activeingredient from the particles, a low molecular weight polymer ispreferred. High molecular weight HPMC is more likely to yield asustained release pharmaceutical dosage form. The molecular weight of awater-soluble cellulose ether is generally expressed in terms of theapparent viscosity at 20° C. of an aqueous solution containing twopercent by weight of said polymer. Suitable HPMC include those having aviscosity from about 1 to about 100 mPa·s, in particular form about 3 toabout 15 mPa·s, preferably about 5 mPa·s The most preferred type of HPMChaving a viscosity of 5 mPa·s., is the commercially available HPMC 29105 mPa·s, because this yields particles from which superior oral dosageforms of compounds of formula (I-A), (I-B) or (I-C) can be prepared aswill be discussed hereunder and in the experimental part.

The weight-by-weight ratio of (a) (i.e. the antiviral compound): (b)(i.e. the water-soluble polymer) is in the range of 1:1 to 1:899,preferably 1:1 to 1:100, more preferably 1:1 to 1:5. In the case of(compound of formula (I-A), (I-B) or (I-C)): (HPMC 2910 5 mPa·s), saidratio preferably ranges from about 1:1 to about 1:3, and optimally isabout 1:1.5 (or 2:3). The most appropriate weight by weight ratio of acompound of formula (I-A), (I-B) or (I-C) to water-soluble polymer(s)may be determined by a person skilled in the art by straightforwardexperimentation. The lower limit is determined by practicalconsiderations. Indeed, given the therapeutically effective amount of acompound of formula (I-A), (I-B) or (I-C) (from about 1 mg to about 1000mg per unit dosage form, preferably about 200 mg to 400 mg or 5 to 200mg per unit dosage form), the lower limit of the ratio is determined bythe maximum amount of mixture that can be processed into one dosage formof practical size. When the relative amount of water-soluble polymer istoo high, the absolute amount of mixture needed to reach the therapeuticlevel will be too high to be processed into one capsule or tablet.Tablets, for example, have a maximum weight of about 1 g, and theextrudate can account for maximally about 90% (w/w) thereof.Consequently, the lower limit of the amount of a compound of formula(I-A), (I-B) or (I-C) over water-soluble polymer will be about 1:899 (1mg of a compound of formula (I-A), (I-B) or (I-C)+899 mg water-solublepolymer).

On the other hand, if the ratio is too high, this means the amount ofthe compound of formula (I-A), (I-B) or (I-C) is relatively highcompared to the amount of water-soluble polymer, then there is the riskthat the compound of formula (I-A), (I-B) or (I-C) will not dissolvesufficiently in the water-soluble polymer, and thus the requiredbioavailability will not be obtained. The degree to which a compound hasdissolved into a water-soluble polymer can often be checked visually: ifthe extrudate is clear then it is very likely that the compound willhave dissolved completely in the water-soluble polymer. It will beappreciated that the upper limit of 1:1 may be underestimated forparticular compounds of formula (I-A), (I-B) or (I-C) and particularwater-soluble polymers. Since this can be established easily but for theexperimentation time involved, solid dispersions wherein the ratio(a):(b) is larger than 1:1 are also meant to be comprised within thescope of the present invention.

The particles according to the present invention can be prepared byfirst preparing a solid dispersion of the components, and thenoptionally grinding or milling that dispersion. Various techniques existfor preparing solid dispersions including melt-extrusion, spray-dryingand solution-evaporation, melt-extrusion being preferred.

The melt-extrusion process comprises the following steps:

a) mixing the components (a) and (b),

b) optionally blending additives with the thus obtained mixture,

c) heating the thus obtained blend until one obtains a homogenous melt,

d) forcing the thus obtained melt through one or more nozzles; and

e) cooling the melt till it solidifies.

The terms “melt” and “melting” should be interpreted broadly. For ourpurposes, these terms not only mean the alteration from a solid state toa liquid state, but can also refer to a transition to a glassy state ora rubbery state, and in which it is possible for one component of themixture to get embedded more or less homogeneously into the other. Inparticular cases, one component will melt and the other component(s)will dissolve in the melt thus forming a solution, which upon coolingmay form a solid solution having advantageous dissolution properties.

One of the most important parameters of melt extrusion is thetemperature at which the melt-extruder is operating. It was found thatthe operating temperature can easily range between about 20° C. andabout 300° C., more preferably about 70° C. and 250° C. The lowertemperature limit depends on the solubility of a compound of formula(I-A), (I-B) or (I-C) in the water-soluble polymer and on the viscosityof the mixture. When the compound of formula (I-A), (I-B) or (I-C) isnot completely dissolved in the water-soluble polymer, the extrudatewill not have the required bioavailability; when the viscosity of themixture is too high, the process of melt extrusion will be difficult. Attemperatures of more than 300° C. the water-soluble polymer maydecompose to an unacceptable level. It may be noted that there is noneed to fear decomposition of a compound of formula (I-A), (I-B) or(I-C) at temperatures up to 300° C. A person skilled in the art willeasily recognize the most appropriate temperature range to be used.

The throughput rate is also of importance because even at relatively lowtemperatures the water-soluble polymer may start to decompose when itremains too long in contact with the heating element.

It will be appreciated that the person skilled in the art will be ableto optimize the parameters of the melt extrusion process within theabove given ranges. The working temperatures will also be determined bythe kind of extruder or the kind of configuration within the extruderthat is used. Most of the energy needed to melt, mix and dissolve thecomponents in the extruder can be provided by the heating elements.

However, the friction of the material within the extruder may alsoprovide a substantial amount of energy to the mixture and aid in theformation of a homogenous melt of the components.

A person skilled in the art will easily recognize the most appropriateextruder, such as, for example, a single screw, a twin screw extruder ora multi-screw extruder, for the preparation of the subject-matter of thepresent invention.

Spray-drying of a solution of the components also yields a soliddispersion of said components and may be a useful alternative to themelt-extrusion process, particularly in those cases where thewater-soluble polymer is not sufficiently stable to withstand theextrusion conditions and where residual solvent can effectively beremoved from the solid dispersion. Yet another possible preparationconsists of preparing a solution of the components, pouring saidsolution onto a large surface so as to form a thin film, and evaporatingthe solvent therefrom.

The solid dispersion product is milled or ground to particles having aparticle size of less than 1500 μm, preferably less than 400 μm, morepreferably less than 250 μm, and most preferably less than 125 μm. Theparticle size proves to be an important factor determining the speedwith which a particular dosage form can be manufactured on a largescale. For instance, for capsules, the particle size may rangepreferably from 100 to 1500 μm; for tablets the particle size ispreferably less than 250 μm. The smaller the particles, the faster thetabletting speed can be without detrimental effects on their quality.The particle size distribution is such that more than 70% of theparticles (measured by weight) have a diameter ranging from about 50 μmto about 1400 μm, in particular from about 50 μm to about 200 μm, morein particular from about 50 μm to about 150, and most in particular fromabout 50 μm to about 125 μm. Particles of the dimensions mentionedherein can be obtained by sieving them through nominal standard testsieves as described in the CRC Handbook, 64^(th) ed., page F-114.Nominal standard sieves are characterized by the mesh/hole width (μm),DIN 4188 (mm), ASTME 11-70 (No), Tyler® (mesh) or BS 410 (mesh) values.Throughout this description, and in the claims hereinafter, particlesizes are designated by reference to the mesh/hole width in μm and tothe corresponding Sieve No. in the ASTM E11-70 standard.

Preferred are particles wherein the compound of formula (I-A), (I-B) or(I-C) is in a non-crystalline phase as these have an intrinsicallyfaster dissolution rate than those wherein part or all of the compoundof formula (I-A), (I-B) or (I-C) is in a microcrystalline or crystallineform.

Preferably, the solid dispersion is in the form of a solid solutioncomprising (a) and (b). Alternatively, it may be in the form of adispersion wherein amorphous or microcrystalline (a) or amorphous ormicrocrystalline (b) is dispersed more or less evenly in a solidsolution comprising (a) and (b).

Preferred particles are those obtainable by melt-extrusion of thecomponents and grinding, and optionally sieving. More in particular, thepresent invention concerns particles consisting of a solid solutioncomprising two parts by weight of a compound of formula (I-A), (I-B) or(I-C) and three parts by weight of hydroxypropyl methylcellulose HPMC2910 5 mPa·s, obtainable by blending said components, melt-extruding theblend at a temperature in the range of 20° C.-300° C., grinding theextrudate, and optionally sieving the thus obtained particles. Thepreparation is easy to perform and yields particles of a compound offormula (I-A), (I-B) or (I-C) that are free of organic solvent.

The particle as described hereinabove may further comprise one or morepharmaceutically acceptable excipients such as, for example,plasticizers, flavors, colorants, preservatives and the like. Saidexcipients should not be heat-sensitive, in other words, they should notshow any appreciable degradation or decomposition at the workingtemperature of the melt-extruder.

In the current formulations (compound of formula (I-A), (I-B) or(I-C):HPMC 2910 5 mPa·s), the amount of plasticizer is preferably small,in the order of 0% to 15% (w/w), preferably less than 5% (w/w). Withother water-soluble polymers though, plasticizers may be employed inmuch different, often higher amounts because plasticizers as mentionedhereinbelow lower the temperature at which a melt of (a), (b) andplasticizer is formed, and this lowering of the melting point isadvantageous where the polymer has limited thermal stability. Suitableplasticizers are pharmaceutically acceptable and include low molecularweight polyalcohols such as ethylene glycol, propylene glycol, 1,2butylene glycol, 2,3-butylene glycol, styrene glycol; polyethyleneglycols such as diethylene glycol, triethylene glycol, tetraethyleneglycol; other polyethylene glycols having a molecular weight lower than1,000 g/mol; polypropylene glycols having a molecular weight lower than200 g/mol; glycol ethers such as monopropylene glycol monoisopropylether; propylene glycol monoethyl ether; diethylene glycol monoethylether; ester type plasticizers such as sorbitol lactate, ethyl lactate,butyl lactate, ethyl glycolate, allyl glycollate; and amines such asmonoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine;triethylenetetramine, 2-amino-2-methyl-1,3-propanediol and the like. Ofthese, the low molecular weight polyethylene glycols, ethylene glycol,low molecular weight polypropylene glycols and especially propyleneglycol are preferred.

Once the extrudate is obtained, it can be milled and sieved, and it canbe used as ingredient to make pharmaceutical dosage forms.

The particles of the present invention can be formulated intopharmaceutical dosage forms comprising a therapeutically effectiveamount of particles. Although, at first instance, pharmaceutical dosageforms for oral administration such as tablets and capsules areenvisaged, the particles of the present invention can also be used toprepare pharmaceutical dosage forms e.g. for rectal administration.Preferred dosage forms are those adapted for oral administration shapedas a tablet. They can be produced by conventional tabletting techniqueswith conventional ingredients or excipients and with conventionaltabletting machines. As mentioned above, an effective antiviral dose ofa compound of formula (I-A), (I-B) or (I-C) ranges from about 1 mg toabout 1000 mg per unit dosage form, and preferably is about 200 to 400mg or 5 to 200 mg per unit dosage form depending on the particularcompound being used. When one considers that the weight-by-weight ratioof (a):(b) is maximally about 1:1, then it follows that one dosage formwill weigh at least 10 to 800 mg. In order to facilitate the swallowingof such a dosage form by a mammal, it is advantageous to give the dosageform, in particular tablets, an appropriate shape. Tablets that can beswallowed comfortably are therefore preferably elongated rather thanround in shape. Especially preferred are biconvex oblate tablets. Asdiscussed hereunder in more detail, a film coat on the tablet furthercontributes to the ease with which it can be swallowed.

Tablets that give an immediate release of a compound of formula (I-A),(I-B) or (I-C) upon oral ingestion and that have good bioavailabilityare designed in such a manner that the tablets disintegrate rapidly inthe stomach (immediate release) and that the particles which areliberated thereby are kept away from one another so that they do notcoalesce, give local high concentrations of a compound of formula (I-A),(I-B) or (I-C) and the chance that the drug precipitates(bioavailability). The desired effect can be obtained by distributingsaid particles homogeneously throughout a mixture of a disintegrant anda diluent.

Suitable disintegrants are those that have a large coefficient ofexpansion. Examples thereof are hydrophilic, insoluble or poorlywater-soluble crosslinked polymers such as crospovidone (crosslinkedpolyvinylpyrrolidone) and croscarmellose (crosslinked sodiumcarboxymethylcellulose). The amount of disintegrant in immediate releasetablets according to the present invention may conveniently range fromabout 3 to about 15% (w/w) and preferably is about 7 to 9%, inparticular about 8.5% (w/w). This amount tends to be larger than usualin tablets in order to ensure that the particles are spread over a largevolume of the stomach contents upon ingestion. Because disintegrants bytheir nature yield sustained release formulations when employed in bulk,it is advantageous to dilute them with an inert substance called adiluent or filler.

A variety of materials may be used as diluents or fillers. Examples arespray-dried or anhydrous lactose, sucrose, dextrose, mannitol, sorbitol,starch, cellulose (e.g. micro-crystalline cellulose Avicel™), dihydratedor anhydrous dibasic calcium phosphate, and others known in the art, andmixtures thereof. Preferred is a commercial spray-dried mixture oflactose monohydrate (75%) with microcrystalline cellulose (25%) which iscommercially available as Microcelac™. The amount of diluent or fillerin the tablets may conveniently range from about 20% to about 40% (w/w)and preferably ranges from about 25% to about 32% (w/w).

The tablet may include a variety of one or more other conventionalexcipients such as binders, buffering agents, lubricants, glidants,thickening agents, sweetening agents, flavors, and colors. Someexcipients can serve multiple purposes.

Lubricants and glidants can be employed in the manufacture of certaindosage forms, and will usually be employed when producing tablets.Examples of lubricants and glidants are hydrogenated vegetable oils, e.ghydrogenated Cottonseed oil, magnesium stearate, stearic acid, sodiumlauryl sulfate, magnesium lauryl sulfate, colloidal silica, talc,mixtures thereof, and others known in the art. Interesting lubricantsand glidants are magnesium stearate, and mixtures of magnesium stearatewith colloidal silica A preferred lubricant is hydrogenated vegetableoil type I, most preferably hydrogenated, deodorized Cottonseed oil(commercially available from Karlshamns as Akofine NF™ (formerly calledSterotex™)). Lubricants and glidants generally comprise 0.2 to 7.0% ofthe total tablet weight.

Other excipients such as coloring agents and pigments may also be addedto the tablets of the present invention. Coloring agents and pigmentsinclude titanium dioxide and dyes suitable for food. A coloring agent isan optional ingredient in the tablet of the present invention, but whenused the coloring agent can be present in an amount up to 3.5% based onthe total tablet weight.

Flavors are optional in the composition and may be chosen from syntheticflavor oils and flavoring aromatics or natural oils, extracts fromplants leaves, flowers, fruits and so forth and combinations thereof.These may include cinnamon oil, oil of wintergreen, peppermint oils, bayoil, anise oil, eucalyptus, thyme oil. Also useful as flavors arevanilla, citrus oil, including lemon, orange, grape, lime andgrapefruit, and fruit essences, including apple, banana, pear, peach,strawberry, raspberry, cherry, plum, pineapple, apricot and so forth,The amount of flavor may depend on a number of factors including theorganoleptic effect desired. Generally the flavor will be present in anamount from about 0% to about 3% (w/w).

As known in the art, tablet blends may be dry-granulated orwet-granulated before tabletting. The tabletting process itself isotherwise standard and readily practiced by forming a tablet fromdesired blend or mixture of ingredients into the appropriate shape usinga conventional tablet press.

Tablets of the present invention may further be film-coated to improvetaste, to provide ease of swallowing and an elegant appearance. Manysuitable polymeric film-coating materials are known in the art. Apreferred film-coating material is hydroxypropyl methylcellulose HPMC,especially HPMC 2910 5 mPa·s. Other suitable film-forming polymers alsomay be used herein, including, hydroxypropylcellulose, andacrylate-methacrylate copolymers. Besides a film-forming polymer, thefilm coat may further comprise a plasticizer (e.g. propylene glycol) andoptionally a pigment (e.g. titanium dioxide). The film-coatingsuspension also may contain talc as an anti-adhesive. In immediaterelease tablets according to the invention, the film coat is small andin terms of weight accounts for less than about 3% (w/w) of the totaltablet weight.

Preferred dosage forms are those wherein the weight of the particles isat least 40% of the total weight of the total dosage form, that of thediluent ranges from 20 to 40%, and that of the disintegrant ranges from3 to 10%, the remainder being accounted for by one or more of theexcipients described hereinabove.

The present invention further concerns a process of preparing particlesas described hereinbefore, characterized by blending the components,extruding said blend at a temperature in the range of 20-300° C.,grinding the extrudate, and optionally sieving the particles.

The invention also concerns solid dispersions obtainable bymelt-extrusion of

-   (a) a compound of formula (I-A), (I-B) or (I-C) or one of its    stereoisomers or a mixture of two or more of its stereoisomers, and-   (c) one or more pharmaceutically acceptable water-soluble polymers.

It is another object of the invention to provide a process of preparinga pharmaceutical dosage form as described hereinbefore, characterized byblending a therapeutically effective amount of particles as describedhereinbefore, with pharmaceutically acceptable excipients andcompressing said blend into tablets or filling said blend in capsules.

Further, this invention concerns particles as described hereinbefore,for use in preparing a pharmaceutical dosage form for oraladministration to a mammal suffering from a viral infection, whereinpreferably a single such dosage form can be administered once daily tosaid mammal.

The present invention also concerns the use of particles according to asdescribed hereinbefore, for the preparation of a pharmaceutical dosageform for oral administration to a mammal suffering from a viralinfection, wherein preferably a single such dosage form can beadministered once daily to said mammal.

The invention also relates to a method of treating a viral infection ina mammal which comprises administering to said mammal an effectiveantiviral amount of a compound of formula (I-A), (I-B) or (I-C),preferably in a single oral dosage form which can be administered oncedaily.

The invention also relates to a pharmaceutical package suitable forcommercial sale comprising a container, an oral dosage form of acompound of formula (I-A), (I-B) or (I-C) as described hereinbefore, andassociated with said package written matter.

The following examples are intended to illustrate the present invention.

EXPERIMENTAL PART 1. Compounds of Formula (I-A) 1.A. Preparation ofIntermediate Compounds Example 1.A1

a) A solution of 2,6-dichlorobenzylchloride (0.102 mol) in1,1-diethylether (10 ml) was added dropwise to magnesium (0.102 mol) in1,1-diethylether (60 ml). The reaction was initiated by adding 2 dropsof 1,2-dibromoethane. After most of magnesium disappeared,2,4,6-trichloropyrimidine (0.051 mol) in 1,1-diethylether (30 ml) wasadded. The mixture was stirred overnight at room temperature. Thesolvent was evaporated and the residue was purified by flash columnchromatography over silica gel (eluent: CH₂Cl₂/hexane 1/2). The desiredfractions were collected and the solvent was evaporated, yielding 3.3 gof (21%) 2,4-dichloro-6-[(2,6-dichloro-phenyl)methyl]pyrimidine (interm.1; melting point (mp.): 106-107° C.).

b) Intermediate (1) (0.0081 mol) in 2-propanol (100 ml) was heated untilcomplete dissolution. The solution was then transferred into a pressuretube and NH₃ gas was bubbled into it for 20 minutes. Then the mixturewas heated to 80° C. for 16 hours. The solvent was evaporated, yieldinga residue of two compounds:2-chloro-[(2,6-di-chloro-phenyl)methyl])pyrimidinamine (interm. 2) and4-chloro-6-[(2,6-dichloro phenyl)methyl]-2-pyrimidinamine (interm. 3).

Example 1.A2

a) Urea (0.03 mol) was added to a mixture of (±)ethyl2,6-chloro-phenyl-α-methyl-β-oxobutanoate (0.02 mol) in NaOC₂H₅ inethanol, (1M; 0.040 mol; 40 ml). The reaction mixture was stirred andrefluxed overnight. The solvent was evaporated, water was added and themixture was neutralized with 0.3 N HOAc. The precipitate was filteredoff and was further triturated with ether and then H₂O, then filteredoff and dried, yielding 2.2 g (39%) of6-[(2,6-dichloro-phenyl)methyl]-5-methyl-2,4(1H,3H)-pyrimidinedione(interm. 4).

b) A mixture of intermediate (4) (0.0095 mol) in phosphoryl chloride (50ml) was stirred and refluxed overnight. Excess of phosphoryl chloridewas then evaporated. Ice-water was added to the residue. A whiteprecipitate was formed, filtered off and dried. The residue was purifiedby flash column chromatography over silica gel (eluent: CH₂Cl₂). Thedesired fractions were collected and the solvent was evaporated,yielding 2.06 g (67%) of2,4-dichloro-6-[(2,6-dichloro-phenyl)methyl]-5-methyl-pyrimidine(interm. 5).

c) 4-chloro-6-[(2,6-dichloro-phenyl)methyl]-5-methyl-2-pyrimidinamine(interm. 6) and

2-chloro-6-[(2,6-dichloro-phenyl)methyl]-5-methyl-4-pyrimidinamine(interm. 7) were prepared from intermediate 5 following the proceduresas described in example A1b.

Example 1.A3

a) To the stirred solution of 2,6-dichlorobenzeneethanimidamide HCl(1:1), (0.0042 mol) in ethanol (20 ml), a solution of sodium (0.013 mol)in ethanol (10 ml) was added dropwise first and then propanedioic acid,diethyl ester (0.0109 mol) was added. The reaction mixture was stirredand refluxed for 4 hours and then stirred at room temperature overnight.After adding another equivalent of propanedioic acid, diethyl ester(stirring and refluxing it overnight), the solvent was evaporated andthe residue was dissolved in water and acidified with 1 N HCl. The solidwas filtered off, washed with water and dried, yielding 0.87 g (76.4%)of 2-[(2,6-dichloro-phenyl)methyl]-4,6-pyrimidinediol (interm. 8).

b) 6-chloro-2-[(2,6-dichloro-phenyl)methyl]4-pyrimidinamine (interm. 9)was prepared starting from intermediate 8 according to the proceduresdescribed in example A1b), A2b) & A2c).

Example 1.A4

4-Amino-1-butanol (1.57 ml) was added to a solution of intermediate (1)(0.008 mol) in 1,4-dioxane (20 ml) under Argon. The reaction mixture wasstirred for 2 hours at room temperature. The solvent was evaporated. Theresidue was purified by flash column chromatography over silica gel(eluent gradient: CH₂Cl₂/CH₃OH: from 100/0 to 98/2). The pure fractionswere collected and the solvent was evaporated, yielding 2.05 g of amixture of4-[[2-chloro-6-[(2,6-dichloro-phenyl)methyl]4-pyrimidinyl]-amino]-1-butanol(interm. 10) and4-[[4-chloro-6-[(2,6-dichloro-phenyl)methyl]-2-pyrimidinyl]amino]-1-butanol(interm. 11).

Example 1.A5

a) Potassium hydroxide/ethanol (10%; 0.035 mol) was added to a solutionof 2,6-dichlorophenol (0.035 mol) in tetrahydrofuran (100 ml). Themixture was stirred and 2,4,6-trichloropyrimidine (0.044 mol) was added.The mixture was stirred overnight at 60° C. The reaction was quenchedwith NaOH 1N solution. The aqueous layers were extracted with EtOAcseveral times and then the organic layers were combined and washed withNaOH 3N and saturated NaCl, dried and concentrated. The residue wasrecrystallized from CH₂Cl₂/hexane. The precipitate was filtered off anddried, yielding 5.98 g 2,4-dichloro-(2,6-dichlorophenoxy)pyrimidine(55%) (interm. 12).

b) Reaction under Argon atmosphere. 2,4,6-trimethylaniline (0.0678 mol)was added to 2,4-dichloropyrimidine (0.0664 mol) in 1,4-dioxane (100ml). N,N-di(1-methylethyl)-etheneamine (0.0830 mol) was added. Thereaction mixture was stirred and refluxed for 4 days and the solvent wasevaporated. The residue was dissolved in CH₂Cl₂, washed with a saturatedNaHCO₃ solution, then dried (Na₂SO₄), filtered and the solvent wasevaporated to give 17.1 g solid residue. This solid was dissolved inCH₂Cl₂:hexane (1:1; 150 ml), and the resulting solution was concentratedto 100 ml, then filtered. The residue was purified by columnchromatography on KP-Sil (eluent: CH₂Cl₂). The desired fractions werecollected and the solvent was evaporated. The less polar fraction wasstirred in CH₂Cl₂ for 3 hours and filtered, yielding 0.44 g4-chloro-N-(2,4,6-trimethylphenyl)-2-pyrimidinamine (intermediate 10). Asecond fraction was recrystallized from acetonitrile, filtered off anddried, yielding 2-chloro-N-(2,4,6-trimethyl-phenyl)-4-pyrimidinamine(intermediate 14).

Example 1.A6

Pyridine (1 ml) was added to a mixture of4-[[4-amino-6-[(2,6-dichlorophenyl)-methyl]-2-pyrimidinyl]amino]benzonitrile(0.00135 mol) in CH₂Cl₂ (19 ml). A solution of chloroethanoyl chloride(0.001375 mol) in CH₂Cl₂ (0.5 ml) was added dropwise on an ice bath. Themixture was stirred at room temperature for 2 hours. More chloroethanoylchloride (0.00625 mol) in CH₂Cl₂ (0.5 ml) was added. The mixture stoodin the refrigerator overnight. The solvent was evaporated. The residuewas treated with a saturated Na₂CO₃ solution and the mixture wasextracted with CH₂Cl₂. The separated organic layer was dried, filteredand concentrated. The residue was purified by flash columnchromatography over silica gel (eluent: CH₂Cl₂CH₃OH/NH₄OH 99/110.1). Thedesired fractions were collected and the solvent was evaporated,yielding 0.22 g (36.5%) of2-chloro-N-[6-[(2,6-dichloro-phenyl)methyl]-2-[(4-cyano-phenyl)amino]-4-pyrimidinyl]acetamide(interm. 13).

Example 1.A7

A mixture of 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.005 mol)and nitryl tetrafluoroborate (0.0025 mol) in acetonitrile (5 ml) wasstirred at room temperature for 4 h. The material was quenched withsaturated bicarbonate (50 ml) on cracked ice. The mixture was allowed toreach room temperature, and the yellow solid was filtered off. The solidwas adsorbed onto silica and purified by column chromatography (eluent:30%, 50%, 60%, 70% CH₂Cl₂ in hexanes). The solvent of the desiredfraction was evaporated and the residue was dried, yielding 0.89 g (64%)of 3-nitro-4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile. (interm. 15)

Example 1.A8

A mixture of 2,6-dichloro-N-(2,4,6-trimethylphenyl)-4-pyrimidinamine(0.00376 mol) in a 2.0 M solution of NH₃ in 2-propanol (25 ml) and a 0.5M solution of NH₃ in dioxane (25 ml) was heated in a pressure sample at110-115° C. for 24 hours. The solvent was evaporated, and the residuewas chromatographed on Biotage (eluent: 1:1 CH₂Cl₂: hexane). The desiredfractions were collected and the solvent was evaporated, yielding amixture of 0.523 g of2-chloro-N4-(2,4,6-trimethylphenyl)-4,6-pyrimidine-diamine (interm. 53)and 0.101 g of 6-chloro-N4-2,4,6-trimethylphenyl)-2,4-pyrimidinediamine.(interm. 16)

Example 1.A9

a) 2,4,6-trichloro-1,3,5-triazine (0.07440 mol) and tetrahydrofuran (100ml) were combined and cooled to −75° C. under Ar atmosphere.4-Aminobenzonitrile (0.07440 mol) was added and the solution was stirredfor 4 hours at −75° C. Triethylamine (0.07440 mol) was added dropwiseand the reaction mixture was allowed to warm up slowly to roomtemperature and stirred for 3 days. After adding 1,4-dioxane (100 ml),the resulting precipitate was collected by filtration, washed withtetrahydrofuran, and dried, yielding 12.74 g4-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]benzonitrile (interm. 17).

b) NaH (0.0113 mol), CH₃CN (30 ml) and 2,6-dichlorophenol (0.0113 mol)were combined and stirred for 15 minutes under Ar atmosphere.Intermediate (17) (0.0113 mol) was added and the reaction mixture wasstirred at room temperature for 16 hours. The reaction mixture wasquenched with ice water (30 ml) and filtered. A precipitate formed inthe filtrate and was filtered off. The resulting solid was washed withH₂O and CH₃CN, then dried, yielding 0.62 g (14.0%) of4-[[4-chloro-6-(2,6-dichlorophenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile(interm. 18).

c) N,N-Diisopropylethylamine (0.00714 mol) was added to a solution of2-chloro-6-methylbenzenamine (0.00714 mol) in 1,4-dioxane (20 ml) underAr flow. A solution of intermediate (17) (0.00714 mol) in 1,4-dioxane (5ml) was added. The reaction mixture was stirred and refluxed for 24hours. The solvent was evaporated and CH₂Cl₂ was added. The organiclayer was washed with a saturated aqueous NaHCO₃ solution, and theresulting precipitate was filtered, yielding 0.56 g (21.1%) of4-[[4-chloro-[(2-chloro-6-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile(interm. 19).

Example 1.A10

a) 2,4,6-Trichloro-1,3,5-triazine (0.0266 mol) was added to 1,4-dioxane(50 ml) under Ar atmosphere. The solution was stirred until it becamehomogeneous, then 2,6-dichlorobenzenamine (0.0266 mol) and K₂CO₃ (0.0362mol) were added. The reaction mixture was stirred at room temperaturefor 3 days. The solvent was evaporated. Water was added to the residueand the aqueous phase was extracted with CH₂Cl₂. The separated organiclayer was washed with brine, dried with potassium carbonate, filteredand the filtrate was evaporated, yielding 7.52 g (91.2%) ofN-(2,6-dichlorophenyl)-4,6-dichloro-1,3,5-triazin-2-amine (interm. 20).

b) 1,4-Dioxane (50 ml), 4-cyanoaniline (0.0243 mol), andN,N-diisopropylethylamine (0.0243 mol) were added to intermediate (20)(0.0243 mol) under Ar atmosphere. The reaction mixture was stirred andrefluxed for 1 week. The reaction was cooled, the solvent was evaporatedand the residue was dissolved in ethyl acetate. The organic phase waswashed with a saturated NaHCO₃ solution and with brine, dried withpotassium carbonate, filtered, and the solvent was evaporated. Theresidue was stirred in a mixture of CH₂Cl₂ and saturated NaHCO₃, and theprecipitate filtered, yielding 2.26 g (23.8%) of4-[[4-chloro-6-[(2,6-dichlorophenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile(interm. 21).

Example 1.A11

Rink Amide resin (15 g; Calbiochem-Novabiochem Corp., San Diego, Calif.;Product No. 010013) was washed in a reaction vessel with CH₂Cl₂ (100ml), N,N-dimethylformamide (200 ml), andN,N-dimethylformamide:piperidine (150 ml:50 ml) was added. The mixturewas agitated for 2 hours, washed with N,N-dimethylformamide, CH₂Cl₂, anddimethylsulfoxide. Intermediate (17) (0.06 mol),N,N-diisopropylethylamine (10.5 ml) and dimethylsulfoxide (200 ml) wereadded and the reaction mixture was agitated for three days, then washedwith N,N-dimethylformamide and CH₂Cl₂, yielding the resin boundintermediate (17).

1.B. Preparation of Compounds of Formula (I-A) Example 1.B1

A mixture of

(*1.A4) (0.004 mol) and 4-amino-benzonitrile (0.0084 mol) were combinedin a sealed tube and heated for 16 hours at 160° C. under Argon. Thereaction mixture was allowed to cool to room temperature and dissolvedin CH₂Cl₂/CH₃OH 90/10 (20 ml) and 5 g of silica gel was added. Afterevaporating the solvent, the residue was purified by flash columnchromatography over silica gel (eluent gradient: CH₂Cl₂/CH₃OH: from100/0 to 97/3). The desired fraction was collected and the solvent wasevaporated, yielding 0.31 g (18.1%) of4-[[4-[(2,6-dichloro-phenyl)methyl]-6-[(3-hydroxypropyl)amino]-2-pyrimidinyl]amino]benzonitrile(comp. 4). (* indicates the example number according to which theintermediate was synthesized)

Example 1.B2

(0.00399 mol) and 4-aminobenzonitrile (0.0012 mol) in1-methyl-2-pyrrolidinone (3 ml) was stirred for 16 hours at 130° C.under Argon. Then, the reaction mixture was cooled to room temperatureand quenched with H₂O (200 ml). A precipitate formed, which was stirredfor 16 hours, and separated by filtration over Celite. The residue wasdissolved in CH₃OH/CH₂Cl₂ (10%, 200 ml), dried over K₂CO₃, filtered, andevaporated. This resulting material was further purified by flash columnchromatography over silica gel (gradient eluent: CH₂Cl₂/CH₃OH from 10010to 95/5). The desired fraction was collected and the solvent wasevaporated, yielding 0.43 g (21.7%) of4-[[6-[(2,6-dichlorophenyl)methyl]-2-[[3-(2-oxo-1-pyrrolidinyl)propyl]-amino]4-pyrimidinyl]amino]benzonitrile(mp. 104-114° C.).

Example 1.B3

HCl/diethyl ether (1N; 2.77 ml) was stirred into a solution of

(*1.A4) (0.00277 mol) in 1-methyl-2-pyrrolidinone (4 ml) under N₂atmosphere. The reaction mixture was heated for 5 minutes. Next,4-aminobenzonitrile (0.0061 mol) was added and the reaction was heatedat 100° C. for 16 hours. Then, the reaction mixture was cooled to roomtemperature and diluted with ethylacetate (10 ml). The organic layer waswashed with NaOH (1 N; 2×100 ml), H₂O (2×100 ml), brine (50 ml),respectively, dried, filtered and the filtrate was evaporated. The crudematerial was purified by flash chromatography (eluent: 2.5-7.5% of CH₃OHcontaining 10% NH₄OH in CH₂Cl₂). The desired fractions were collectedand the solvent was evaporated. The residue was dried, yielding 0.160 g(12.0%) of4-[[4-[(2,6-dichloro-phenyl)methyl]-6-[[2-(1-pyrrolidinyl)ethyl]amino]-2-pyrimidinyl]amino]benzonitrile(comp. 14; mp. 80-85° C.).

Example 1.B4

A slurry of

(*1.A2b) (0.005 mol) in CH₂Cl₂ (150 ml) was stirred rapidly and cooledto 0° C. under nitrogen. BBr₃ (0.015 mol) was introduced by syringe. Thereaction mixture was stirred rapidly for two hours. The reaction mixturewas recooled to 0° C. and quenched with NaOH (aq. 1 N, 25 ml). Thebiphasic partial quench mixture gives a precipitate which was filteredoff and dried, yielding 2.5 g (91%) of4-[[4-[(2,6-dichloro-phenyl)methyl]-6-hydroxyamino)-2-pyrimidinyl]amino]benzonitriledihydrobromide.pentahydrate (comp. 12; mp. 240-244° C.).

Example 1.B5

1,1-Dimethoxy-N,N-dimethylmethanamine (0.152 mol) was added to4-[[4-amino-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]benzonitrile(0.0008 mol). The mixture was stirred at room temperature for 2 days andthen concentrated. The crude product was purified by flashchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 99/1). The desiredfraction was collected and the solvent was evaporated. The resultingresidue was triturated with hexane, yielding 0.15 g (42%) ofN-[2-[(4-cyano-phenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-4-pyrimidinyl]-N,N-dimethylmethanimidamide(mp. 175-180° C.).

Example 1.B6

Piperidine (0.12 ml) was added to a mixture of intermediate (13)(0.00047 mol) in terahydrofuran (20 ml). The mixture was stirred at roomtemperature for 4 hours. More piperidine (0.14 ml) was added. Themixture was stirred for another 2 hours. The solvent was evaporated. Theresidue was purified by flash column chromatography over silica gel(CH₂Cl₂/CH₃OH/NH₄OH 99/1/0.1). The desired fractions were collected andthe solvent was evaporated, yielding 0.05 g (21.5%) ofN-[6-[(2,6-di-chloro-phenyl)methyl]-2-[(4-cyano-phenyl)amino]4-pyrimidinyl]-1-piperidine-acetamide(mp. 175-180° C.).

Example 1.B7

Pyridine (0.014 mol) was added to a mixture of4-[[4-amino-6-[(2,6-dichlorophenyl)-methyl]-2-pyrimidinyl]amino]benzonitrile(0.0013 mol) in CH₂Cl₂. A solution of octanoyl chloride (1.5 equiv) inCH₂Cl₂ (0.5 ml) was added dropwise. The mixture was stirred at roomtemperature for 2 hours. More octanoyl chloride (3.5 equiv) in CH₂Cl₂was added dropwise. The mixture was stirred. The solvent was thenevaporated. The residue was treated with a saturated aqueous NaHCO₃solution and the mixture was extracted with CH₂Cl₂. The separatedorganic layer was dried, filtered and the solvent was evaporated to givethe crude product. The residue was recrystallized from CHCl₃ and hexane,yielding 0.443 g (68.6%) ofN-[6-[(2,6-dichloro-phenyl)-methyl]-2-[(4-cyano-phenyl)amino]4-pyrimidinyl]octanamide(mp. 135-137° C.).

Example 1.B8

a) A mixture of intermediate 14 (0.082 mol) and 5.4 N HCl in 2-propanol(0.086 mol) in water (300 ml) was stirred and warmed to 40-45° C. over30 minutes. 4-Amino-benzonitrile (0.242 mol) was added at 40-45° C. Thereaction mixture was stirred and refluxed for 4.5 hours, then cooled toroom temperature. The mixture was alkalized by portionwise addition ofNaHCO₃. This mixture was extracted with ethylacetate. The organic layerwas separated, washed with brine, dried, filtered and the solvent wasevaporated. This fraction was stirred in ethanol p.a (100 ml), filteredoff, washed with ethanol (50 ml), then dried, yielding 23.1 g (86%)4-[[4-[(2,4,6-trimethylphenyl)-amino]-2-pyrimidinyl]amino]benzonitrile(comp. 17).

b) A mixture of 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.021mol) and HCl in 2-propanol (0.0095 mol) in water (30 ml) was stirred forone hour at 45° C.4-amino-3,5-dimethyl-benzonitrile (0.025 mol) wasadded and the reaction mixture was stirred and refluxed overnight. Themixture was cooled to room temperature, then neutralized with NaHCO₃.This mixture was extracted with ethylacetate. The separated organiclayer was washed with brine, dried, filtered and the solvent evaporated.The residue was crystallized from CH₃CN, filtered off and dried. Theresidue was stirred in boiling CH₂Cl₂ (20 ml), then filtered off anddried. The residue was crystallized from methyl isobutyl keton, filteredoff and dried, yielding 0.3 g of4-[[2-[(cyanophenyl)amino]-4-pyrimidinyl]amino]-3,5-dimethylbenzonitrile(comp. 25).

Example 1.B9

a) 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.003 mol),2,6-dibromo-4-methyl-benzenamine (0.006 mol) and 1 M HCl in diethylether (4.5 ml) in 1,4-dioxane (10 ml) were combined in a tube and heatedunder Ar until all diethyl ether had evaporated. The tube was sealed andheated at 170° C. for 2.5 days. Silica gel was added, and the solventwas evaporated. The residue was purified by flash column chromatographyover silica gel (eluent gradient: CH₂Cl₂:CH₃OH:NH₄OH 100:0:0 to99:0.9:0.1). The desired fractions were collected and the solvent wasevaporated. The residue was recrystallized from acetonitrile, filteredoff and dried, yielding 0.22 g (15.9%) of4-[[4-[(2,6-dibromo-4-methylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile.

b) 4-[[4-[(4-chloro-5-methyl-2-pyrimidinyl]amino]benzonitrile (0.01541mol), 4-amino-3,5-dimethyl-benzonitrile (0.00219 mol),1-methyl-2-pyrrolidinone (4 ml), 1,4-dioxane (15 ml) anddiisopropylethylamine (0.0154 mol) were combined in a flask under astream of argon and heated at 160-230° C. for 16 hours. CH₂Cl₂ and 1NNaOH were added, and the mixture was stirred 1 hour and filtered to givea brown solid (!). The CH₂Cl₂ filtrate was separated and was evaporatedand purified by flash column chromatography (eluent: 2% CH₃OH/CH₂Cl₂).The desired fractions were combined, evaporated and the residue wasstirred in CH₂Cl₂. The solid precipitate was filtered off, combined withthe brown solid (!) and recrystallized from CH₃CN. The precipitate wasfiltered off and dried, yielding 1.57 g (29%) of4-[[2-[(4-cyanophenyl)amino]-5-methyl-4-pyrimidinyl]amino]-3,5-dimethylbenzonitrile(comp. 52).

c) 2-[(4-cyanophenyl)amino]-4-pyrimidinyl trifluoromethanesulfonate(0.0022 mol) and 2,6-dichloro-4-trifluoromethyl)-benzenamine (0.0044mol) were combined in 1,4-dioxane (2.5 ml) and heated in a sealed-tubeunder Ar at 170° C. for 40 hours. The reaction mixture was allowed tocool to room temperature. Silica gel was added, and the solvent wasevaporated. The residue was purified by flash column chromatography oversilica gel (eluent gradient: CH₂Cl₂:CH₃OH:NH₄OH 100:0:0 to 97:2.7:0.3).The desired fractions were collected and the solvent was evaporated. Theresidue was recrystallized from CH₃CN, filtered off and dried, yielding0.086 g (9.2%) of4-[[4-[[2,6-dichloro-4-(trifluoromethyl)-phenyl]amino]-2-pyrimidinyl]amino]benzonitrile(comp. 23).

Example 1.B10

To a suspension of NaH (0.006 mol) in 1,4-dioxane (30 ml),2,4,6-trimethyl-phenol (0.006 mol) was added. The mixture was stirredfor 15 minutes at room temperature, and a clear solution formed.4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.004 mol) was added, andthe reaction mixture was heated to reflux under Argon for 15 hours. Thereaction mixture was allowed to cool to room temperature, 0.5 ml ofwater was added, followed by 4 g of silica gel, and the solvent wasevaporated. The residue was purified by flash column chromatography oversilica gel (eluent gradient: CH₂Cl₂:CH₃OH 100:0:0 to 97:3). The purefractions were collected and the solvent was evaporated, yielding 1.18 g(89.4%) of4-[[4-(2,4,6-trimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile (comp.20).

Example 1.B11

4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(0.0015 mol) was stirred in boiling ethanol (8 ml). 6 M HCl in2-propanol (0.0015 mol) was added and the salt was allowed tocrystallize out overnight at room temperature. The precipitate wasfiltered off, washed with 2-propanol and dried, yielding 0.47 g (86%) of4-[[4-[(2,4,6-trimethyl-phenyl)amino]-2-pyrimidinyl]amino]benzonitrilehydrochloride (1:1) (comp. 31).

Example 1.B12

A mixture of4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(0.00303 mol) and NaBO₃.4H₂O (0.00911 mol) in CH₃OH (30 ml) and H₂O (10ml) was stirred and refluxed for 4 days. The reaction mixture wascooled. The precipitate was filtered off and the precipitate (!) waspurified by flash column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH gradient from 100/0 to 95/5). The desired fractions werecollected and the solvent was evaporated, yielding 0.586 g (56%) of4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide(comp. 40). The filtrate (!) was purified by reversed-phase HPLC (eluentgradient: ((0.5% ammoniumacetate in H₂O)/CH₃CN 90/10)/CH₃OH/CH₃CN (0minutes) 75/25/0, (44 minutes) 0/50/50, (57 minutes) 0/0/100, (61.1-70minutes) 75/25/0). Three desired fraction groups were collected andtheir solvent was evaporated, yielding 0.18 g of4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide,N3-oxide (comp. 49) and 0.030 g of4-[[4-(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]-amino]benzamide,N1-oxide.

Example 1.B13

a) A mixture of4-[[4-chloro-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]-amino]benzonitrile(*A9c) (0.00137 mol) and NH₃ in 1,4-dioxane (0.5 M; 0.00548 mol) washeated in a pressure vessel at 100° C. for 6 days. The solvent wasevaporated and the residue was dissolved in CH₂Cl₂, washed with asaturated aqueous NaHCO₃ solution, dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 100/0, 99/1 and 98/2). The desiredfractions were collected and the solvent was evaporated. The residue wasrecrystallized from toluene. The precipitate was filtered and dried,yielding 0.29 g (61.4%) of4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile.

b) As an alternative for the preparation of this compound, a mixture of4-[[4-chloro-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile(0.0230 mol) in NH₃ in 2-propanol (2.0 M; 60 ml) and NH₃ in 1,4-dioxane(0.5 M; 20 ml) was heated at 95° C. for 21 hours. The solvent wasevaporated. The residue was dissolved in ethyl acetate, washed with 1 NNaOH, water and brine, dried, filtered and the filtrate was evaporated.The residue was recrystallized with acetonitrile, yielding 5.25 g(66.1%) of4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile.

c)

(0.00150 mol) and 0.5 M NH₃ in 1,4-dioxane (0.015 mol) were added into apressure flask. The reaction mixture was heated to 40° C. After 5 days,the reaction was cooled to room temperature. 2.0 M NH₃ in 2-propanol(0.015 mol) was added, and the reaction was returned to 40° C. Thereaction was diluted with diethylether and extracted with cold 1 M NaOH.The aqueous layer was extracted twice more, and the organic phases werecombined. The insoluble material was filtered off and washed withdiethylether, which dissolved most of the material into the filtrate.The filtrate was combined with the organic phases and this solution wasdried, filtered and the solvent evaporated. The residue was purifiedover silica gel flash chromatography, eluting with 4:1CH₂Cl₂:diethylether to 100% diethylether. The resulting material wasrecrystallized in tetrahydrofuran/CH₃CN, filtered off and dried,yielding 0.36 g (67%) of4-[[4-amino-1-[(2,4,6-timethylphenyl)azo]-1,3,5-triazin-2-yl]amino]benzonitrile.

Example 1.B14

O-(Trimethylsilyl)-hydroxylamine (0.0282 mol) was added to

(*1.A10b) (0.00282 mol) in 1,4-dioxane (10 ml). The reaction mixture wasstirred at room temperature for 2 days. The solvent was evaporated. Theresidue was dissolved in ethyl acetate, washed with 1 N HCl, washed witha saturated aqueous NaHCO₃ solution and with brine, dried, filtered andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel ((I) eluent gradient: CH₂Cl₂CH₃OH 98/2 to9614 and (II) eluent gradient: CH₂Cl₂/CH₃OH 100/0, 99/1 and 98/2) Thedesired fractions were collected and the solvent was evaporated. Theresidue was recrystallized from acetonitrile. The precipitate wasfiltered off and dried, yielding 0.32 g (29.2%) of4-[[[6-(2,6-dichlorophenylamino)-4-(hydroxylamino)]-1,3,5-triazin-2-yl]amino]benzonitrile.

Example 1.B15

Tetrahydrofuran (10 ml) and 2,5-dimethylphenol (0.00818 mol) were addedto NaH (0.00859 mol). The mixture was stirred for 30 minutes at roomtemperature. Then, a solution of intermediate (17) (0.00818 mol) intetrahydrofuran (100 ml) was added. The reaction mixture was stirred for16 hours. Then, the solvent was evaporated and NH₃ in 1,4-dioxane (50ml) was added. The resulting reaction mixture was stirred for 16 hours.The solvent was evaporated; and, the resulting residue was treated withH₂O/CH₂Cl₂, stirred, and filtered. A precipitate formed in the filtrateand was filtered off, yielding 0.42 g of fraction 1. The resultingfiltrate was dried over K₂CO₃ and concentrated. The residue was purifiedby flash column chromatography (eluent: CH₃OH/CH₂Cl₂ 2.5/97.5). Thedesired fractions were collected and the solvent was evaporated,yielding 2.89 g of fraction 2. Fractions 1 and 2 were combined andrecrystallized from CH₃CN. The precipitate was filtered off and dried,yielding 1.16 g (42.7%) of4-[[4-amino-6-(2,5-dimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile.

Example 1.B16

To a reaction vessel under Ar were added resin bound intermediate (17)as prepared in example A 11 (0.00015 mol), a solution of silver triflate(0.075 g) in dimethylsulfoxide (1 ml), 4-bromo-2-chloro-6-methylphenol(0.0027 mol), dimethylsulfoxide (3 ml), and 1.0M sodiumbis(trimethylsilyl)amide and disilazane(1,1,1-trimethyl-N-(trimethylsilyl)-silanamine, sodium salt) (3 ml). Thereaction mixture was heated at 95° C. for 12 hours. The sample wasfiltered, and the resin was washed with N,N-dimethylformamide (3×),CH₂Cl₂, N,N-dimethylformamide, CH₃OH, and CH₂Cl₂ (3×). The sample wascleaved twice with 10% trifluoroacetic acid in CH₂Cl₂ (5 ml, then 3 ml).The solvent was evaporated under N₂. Purification by reverse phase HPLCyielded 0.0055 g of4-[[4-amino-6-(4-bromo-2-chlor-6-methylphenoxy)-1,3,5-triazin-2-yl]-amino]benzonitrile.

Example 1.B17

To a flask under Ar were added the resin bound intermediate (17) asprepared in example A 11 (0.00015 mol), CsCO₃ (0.975 g),4-chloro-2,6-dimethylphenol (0.0038 mol), dimethylsulfoxide (2 ml) and 1ml of a solution of silver triflate (0.075 g) in dimethylsulfoxide (1ml). Ar was bubbled through the reaction mixture for 1 minute. The flaskwas heated at 95° C. for 20 hours. The sample was then filtered, andwashed with N,N-dimethylformamide (2×), water (3×),N,N-dimethylformamide (2×), CH₃OH (1×), and CH₂Cl₂ (3×). The sample wasthen cleaved with 10% trifluoroacetic acid in CH₂Cl₂ (3 ml), yielding0.0043 g of4-[[4-amino-6-(4-chloro-2,6-dimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile.

Example 1.B18

To a flask under Ar were added intermediate (17) (0.00752 mol),N,2,4,6-tetramethylbenzenamine (0.00752 mol) in 1,4-dioxane (20 ml) andN,N-diisopropylethylamine (0.00752 mol). The reaction mixture wasstirred and refluxed for 20 hours and the solvent was evaporated. Theresidue was transferred into a pressure vessel with 0.5M NH₃ in1,4-dioxane (0.005 mol) and 2.0M NH₃ in 2-propanol (0.040 mol) and themixture was heated at 115° C. for 24 hours. The solvent was evaporated,the residue dissolved in CH₂Cl₂, washed with 1N NaOH and water, driedwith potassium carbonate, filtered, and the solvent evaporated. Theresidue was recrystallized two times with acetonitrile, filtered off anddried, yielding 1.0 g (37%) of4-[[4-amino-6-[methyl-(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile(comp. 76).

Example 1.B19

4,6-dichloro-N-(2,6-dibromo-4-methylphenyl)-1,3,5-triazin-2-amine(0.00651 mol), was dissolved in 1,4-dioxane (30 ml). Sequentially,4-aminobenzonitrile (0.0066 mol) and N,N-diisopropylethylamine (0.0066mol) were added, and the clear solution was heated to reflux for 4 days.The reaction was allowed to cool to room temperature overnight, and themixture was diluted with ethyl acetate and treated with cold 1 M NaOH.The layers were separated, and the organic phase was re-extracted withfresh 1 M NaOH. The combined aqueous phases were treated with solid NaOHto maintain pH>10 and backwashed with ethyl acetate (2×). The combinedorganic phases were dried, filtered and concentrated. The residue wasseparated and purified by flash column chromatography over silica gel(eluent: CH₂Cl₂). The desired fractions were combined, treated withCH₃CN, triturated with CH₃CN, filtered off and dried, yielding 0.30 g(8.0%) of4-[[4-amino-[(2,6-dibromo-4-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile.

Example 1.B20

Intermediate (17),1-(2,3-dihydro-4-hydroxy-7-methyl-1H-inden-5-yl)-ethanone, Cs₂CO₃, and1,4-dioxane were added to a reaction vessel under Ar and heated 100° C.for 48 hours while the sample was slightly vortexed. The sample wascooled, and NH₃ in isopropanol was added. The reaction was heated at100° C. in a sealed tube for 48 hours. The reaction mixture was cooledand water (3 ml) was added to dissolve Cs₂CO₃. The sample was filteredand purified by HPLC, yielding4-[[4-[(5-acetyl-2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-amino-1,3,5-triazin-2-yl]amino]benzonitrile.

1.C. HIV Activity of the Compounds of Formula (I-A) Example 1.C.1

A rapid, sensitive and automated assay procedure was used for the invitro evaluation of anti-HIV agents. An HIV-1 transformed T4-cell line,MT-4, which was previously shown (Koyanagi et al., Int. J. Cancer, 36,445-451, 1985) to be highly susceptible to and permissive for HIVinfection, served as the target cell line. Inhibition of the HIV-inducedcytopathic effect was used as the end point. The viability of both HIV-and mock-infected cells was assessed spectrophotometrically via the insitu reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-phenyltetrazoliumbromide (MTT). The 50% cytotoxic concentration (CC₅₀ in μM) was definedas the concentration of compound that reduced the absorbance of themock-infected control sample by 50%. The percent protection achieved bythe compound in HIV-infected cells was calculated by the followingformula:

${\frac{\left( {OD}_{T} \right)_{HIV} - \left( {OD}_{C} \right)_{HIV}}{\left( {OD}_{C} \right)_{MOCK} - \left( {OD}_{C} \right)_{HIV}}\mspace{14mu}{expressed}\mspace{14mu}{in}\mspace{14mu}\%},$whereby (OD_(T))_(HIV) is the optical density measured with a givenconcentration of the test compound in HIV-infected cells; (OD_(C))_(HIV)is the optical density measured for the control untreated HIV-infectedcells; (OD_(C))_(MOCK) is the optical density measured for the controluntreated mock-infected cells; all optical density values weredetermined at 540 nm. The dose achieving 50% protection according to theabove formula was defined as the 50% inhibitory concentration (IC₅₀ inμM). The ratio of CC₅₀ to IC₅₀ was defined as the selectivity index(SI). The compounds of formula (I-A) were shown to inhibit HIV-1effectively. Particular IC₅₀, CC₅₀ and SI values are listed in Table 1below.

TABLE 1 Co. IC₅₀ CC₅₀ Co. IC₅₀ CC₅₀ No. (μM) (μM) SI No. (μM) (μM) SI 30.027 49.7 1860 28 0.0063 45.8 7275 4 0.016 37.4 2558 29 0.0007 0.5 7058 0.315 >100 >317 30 0.0036 >100 >27777 9 0.094 56.2 598 340.010 >100 >9523 10 0.020 24.4 1192 35 0.0021 1.9 911 11 0.037 58.6 158736 0.0033 5.2 1580 14 0.005 7.8 1557 37 0.0030 9.6 3188 12 0.003 9.02857 38 0.0028 0.4 144 13 0.006 53.6 8642 39 0.0031 4.8 1547 5 0.01750.6 2910 41 0.011 8.7 771 6 0.035 12.2 346 42 0.0011 >100 >90909 10.001 47.9 59935 43 0.0026 0.4 151 2 0.042 43.4 1038 44 0.0008 0.4 54115 0.004 >100 >27027 45 0.012 9.3 753 16 0.058 45.2 786 46 0.002 0.4 2087 0.518 52.0 100 47 0.010 >100 >9803 17 0.001 2.08 2314 48 0.0031 2.2711 31 0.0006 1.3 2111 51 0.0027 2.1 767 19 0.0007 0.8 1153 52 0.00070.4 619 20 0.0029 >100 >34482 18 0.0035 48.1 13743 21 0.0012 >100 >8333332 0.0022 11.1 5064 22 0.0032 8.7 2716 33 0.0006 7.7 12783 23 0.008519.9 2347 50 0.0031 5.8 1885 24 0.001 1.4 1367 40 0.075 0.8 10 25 0.00044.7 11632 27 0.022 >100 4555 26 0.0006 5.8 9641 53 0.0034 18.6 5476 540.003 33.8 10899 69 0.002 1.7 859 55 0.005 49.9 10187 71 0.004 57.313349 56 0.001 44.0 33826 73 0.003 48.0 16561 57 0.001 6.3 4480 74 0.00148.5 80824 58 0.006 8.1 1372 75 0.010 8.2 860 59 0.004 40.6 11285 760.003 51.7 16164 60 0.001 7.6 7614 77 0.001 5.9 11848 66 0.001 32.124712 78 0.003 47.0 17431 67 0.005 >10.0 >1851 70 0.007 30.0 4534 680.002 12.2 6102 72 0.001 54.1 45129

2. Compounds of Formula (I-B) 2.A. Preparation of the IntermediateCompounds Example 2.A1

Reaction under argon atmosphere. A solution of2,4,6-trimethylbenzenamine (0.00461 mol) in 1,4-dioxane (5 ml) was addedto a solution of 5-bromo-2,4-dichloropyrimidine (0.00439 mol) in1,4-dioxane (5 ml). N,N-bis(1-methylethyl)ethanamine (0.00548 mol) wasadded. The reaction mixture was stirred and refluxed for 20 hours. Thesolvent was evaporated. The residue was dissolved in ethyl acetate,washed with a saturated aqueous sodium bicarbonate solution, water andbrine, dried with sodium sulfate, filtered, and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: 1:5, 1:2 and 1:1 CH₂Cl₂: hexane). Two pure fractiongroups were collected and their solvent was evaporated, yielding 0.35 g(24%) of 5-bromo-4-chloro-N-(2,4,6-trimethylphenyl)-2-pyrimidinamine(interm. 1) and 0.93 g (65%) of5-bromo-2-chloro-N-(2,4,6-trimethylphenyl)-4-pyrimidinamine (interm. 2).

Example 2.A2

a) 4-Hydroxy-5-chloro-2-methylthiopyrimidine (0.0156 mol) and4-aminobenzonitrile (0.078-mol) were combined as a melt and stirred at180-200° C. for 6 hours. The reaction mixture was cooled, and trituratedsequentially with boiling CH₂Cl₂ and CH₃CN to obtain 95% pure compound,which was dried, yielding 1.27 g (33%) of4-[(5-chloro-4-hydroxy-2-pyrimidinyl)amino]benzonitrile (interm. 3;mp.>300° C.).

b) POCl₃ (10 ml) was added to intermediate (3) (0.0028 mol). The flaskwas equipped with a condenser and heated to 80° C. for 35 minutes. Thematerial was quenched on ice and allowed and the resulting precipitatewas collected and washed with water (50 ml). The sample was dried. Afraction thereof was further purified by column chromatography. The purefractions were collected and the solvent was evaporated, yielding4-[(4,5-dichloro-2-pyrimidinyl)amino]benzonitrile (interm. 4).

c) The mixture of intermediate (4) (0.0132 mol) in tetrahydrofuran (75ml) and CH₂Cl₂ (10 ml) was stirred for 15 min. HCl in diethyl ether(0.0145 mol) was added slowly, and the mixture was stirred for 5minutes. The solvent was removed under reduced pressure, yielding 3.98 gof 4-[(4,5-dichloro-2-pyrimidinyl)amino]benzonitrile monohydrochloride(interm. 5).

Example 2.A3

a) 2,4,5,6-tetrachloropyrimidine (0.0134 mol), 1,4-dioxane (30 ml),2,4,6-trimethyl aniline (0.0134 mol), andN,N-bis(1-methylethyl)ethanamine (0.0136 mol) were added to a flaskunder argon and stirred at 55° C. for 16 hours. The solvent wasevaporated, and the residue was dissolved in CH₂Cl₂, then purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/hexane 1/4, and1/2). The desired fractions were collected and their solvent wasevaporated, yielding 0.15 g4,5,6-trichloro-N-(2,4,6-trimethylphenyl)-2-pyrimidinamine (interm. 6)and 3.15 g 2,5,6-trichloro-N-(2,4,6-trimethylphenyl)-4-pyrimidinamine(interm. 7).

b) A mixture of intermediate 7 (0.00474 mol) in NH₃, (2.0 M in2-propanol; 20 ml) was heated in a pressure vessel at 75-80° C. for 40hours. The temperature was increased to 110-115° C. The solvent wasevaporated to produce 1.85 g of residue. The sample was heated with NH₃,(0.5 M in 1,4-dioxane; 20 ml) at 125° C. for 18 hours. The solvent wasevaporated, yielding 1.7 g of a mixture of two isomers, i.e.2,5-dichloro-N4-(2,4,6-trimethylphenyl)-4,6-pyrimidinediamine (interm.8) and 5,6-dichloro-N4-(2,4,6-trimethylphenyl)-2,4-pyrimidinediamine(interm. 9).

Example 2.A4

a) A mixture of 4-[(1,4-dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile,(0.12 mol) in POCl₃ (90 ml) was stirred and refluxed under Argon for 20minutes. The reaction mixture was slowly poured onto 750 ml ice/water,and the solid was separated by filtration. The solid was suspended in500 ml water, and the pH of the suspension was adjusted to neutral byadding a 20% NaOH solution. The solid was again separated by filtration,suspended in 200 ml 2-propanone, and 1000 ml CH₂Cl₂ was added. Themixture was heated until all solid had dissolved. After cooling to roomtemperature, the aqueous layer was separated, and the organic layer wasdried. During removal of the drying agent by filtration, a white solidformed in the filtrate. Further cooling of the filtrate in the freezer,followed by filtration, yielded 21.38 g (77.2%) of4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (interm. 10).

b) Intermediate (10) (0.005 mol), 1-bromo-2,5-pyrrolidinedione (0.006mol) and trichloromethane (10 ml) were combined in a sealed tube andheated at 100° C. overnight. The reaction mixture was allowed to cool toroom temperature. Silica gel (2 g) was added, and the solvent wasevaporated. The residue was purified by flash column chromatography oversilica gel (eluent: CH₂Cl₂/hexanes 9/1). The pure fractions werecollected and the solvent was evaporated, yielding 1.31 g (84.5%) of4-[(5-bromo-4-chloro-2-pyrimidinyl)amino]benzonitrile (interm. 11).

Example 2.A5

To a flask under Argon was added 4-amino-2,5,6-trichloropyrimidine(0.08564 mol), 4-amino-benzonitrile (0.1071 mol),1-methyl-2-pyrrolidinone (17 ml) and HCl in diethylether (1M; 85.6 ml).The mixture was placed in an oil bath at 130° C. under a stream ofnitrogen until the ether was gone. An additional 10 ml of1-methyl-2-pyrrolidinone was added The mixture was heated at 145° C. for16 hours under argon. 1,4-Dioxane was added. The mixture was refluxed,cooled, then filtered. The filtrate was evaporated. The residue wasdissolved in CH₂Cl₂, washed with 1 N NaOH, then filtered. The solid wasdissolved in 2-propanone, evaporated onto silica gel, andchromatographed using 1-3% 2-propanone in hexane as eluent. The purefractions were collected and the solvent was evaporated, yielding 1.63 g(6.8%) of 4-[(4-amino-5,6-dichloro-2-pyrimidinyl)amino]benzonitrile(interm. 12).

2.B. Preparation of the Final Compounds of Formula (I-B) Example 2.B1

a) To a flask under argon containing intermediate (1) (0.00107 mol) wasadded ether. To this homogeneous solution was added HCl/diethylether(1M; 0.00109 mol). The solvent was evaporated and 1,4-dioxane (35 ml)and 4-aminobenzonitrile (0.00322 mol) were added. The reaction mixturewas stirred and refluxed for 4 days. The solvent was evaporated. Theresidue was dissolved in CH₂Cl₂, washed with a saturated sodiumbicarbonate solution, dried, filtered and the solvent was evaporated togive 0.79 g of amber oil. The oil was purified by reverse phase HPLC.The desired fractions were collected and the solvent was evaporated,yielding residues 1 and 2. Residue 1 was purified by columnchromatography over silica gel (eluent: 0 and 2% CH₃OH:CH₂Cl₂). The purefractions were collected and the solvent was evaporated, yielding 0.0079g (2.0%) of4-[[5-chloro-2-[(2,4,6-trimethylphenyl)amino]4-pyrimidinyl]amino]benzonitrile(compound 1).

Residue 2 was purified by column chromatography over silica gel (eluent:0 and 2% CH₃OH:CH₂Cl₂). The pure fractions were collected and thesolvent was evaporated, yielding 0.0044 g (1.0%) of4-[[5-bromo-2-[(2,4,6-trimethylphenyl)amino]4-pyrimidinyl]amino]benzonitrile(compound 2).

b) To a flask containing intermediate 2 (0.00285 mol) was added ether.To this homogeneous solution was added HCl in diethyl ether (1M; 0.00855mol). The solvent was evaporated and 1,4-dioxane (20 ml) was added.Finally, 4-aminobenzonitrile (0.00291 mol) and 1,4-dioxane (15 ml) wereadded and the reaction mixture was stirred and refluxed for seven days.The solvent was evaporated, the residue dissolved in CH₂Cl₂, washed with1 M NaOH, and the solvent evaporated. The residue was dissolved inCH₂Cl₂ (10 ml) and the precipitate was filtered off and dried, yielding0.15 g (13%) of4-[[5-bromo-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(comp. 3).

Example 2.B2

a) A 3:1 mixture of intermediate (8) and intermediate (9) [as preparedin example A3b] and 4-aminobenzonitrile (0.01422 mol) was heated in apressure vessel at 180° C. for 5 hours. The sample was partitionedbetween CH₂Cl₂ and diluted NaHCO₃, dried over K₂CO₃, filtered, andevaporated. CH₃CN was stirred in, the resulting precipitate removed byfiltration. The filtrate was further purified by reverse phase HPLC. Thepure fractions were collected and the solvent was evaporated, yielding0.17 g of4-[[4-amino-5-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitriletrifluoroacetate (1:1) (comp. 4).

Example 2.B3

HCl in diethylether (1M; 0.0045 mol) was added to a suspension ofintermediate (4) (0.003 mol) in 1,4-dioxane (5 ml), stirred under argonin a sealable tube. The mixture was warmed to evaporate thediethylether, and 2,4,6-trimethylbenzenamine (0.009 mol) was added. Thetube was sealed, and the reaction mixture was heated to 150° C. for 12hours. The reaction mixture was allowed to cool to room temperature.Sequentially, silica gel (2.2 g) and CH₃OH (50 ml) were added. Afterevaporating the solvent, the residue was purified by flashchromatography (eluent gradient: CH₂Cl₂:CH₃OH:NH₄OH 99.5:0.45:0.05 up to99:0.9:0.1). The pure fractions were collected and the solvent wasevaporated. The residue was dried, yielding 0.80 g (73.4%) of4-[[5-chloro-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(comp. 5).

Example 2.B4

A mixture of intermediate (5) (0.0025 mol) and2,6-dibromo-4-methylbenzenamine (0.0075 mol) in 1,3-dioxane (5.0 ml) ina sealed tube under argon was heated and stirred at 160° C. for 16hours. The reaction mixture was concentrated by rotary evaporation ontosilica gel (2.0 g). The material was purified by flash chromatography(eluent 1:1 hexanes: CH₂Cl₂; neat CH₂Cl₂; 0.5%, 1% (10% NH₄OH in CH₃OH)in CH₂Cl₂) for 90% purity. Recrystallization afforded 0.15 g (12.2%) of4-[[5-chloro-4-[(2,6-dibromo-4-methylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(comp. 10; 95% purity).

Example 2.B5

NaH (0.0075 mol; 60% suspension in oil) was added to a suspension of2,4,6-trimethylphenol (0.0075 mol) in 1,4-dioxane (5 ml) in a sealabletube under argon. The mixture was stirred for 15 minutes, andintermediate (4) (0.0025 mol) was added. The tube was sealed, and thereaction mixture was heated to 150° C. for 15 hours. The reaction wasallowed to cool to room temperature. After silica gel (2.0 g) was added,the solvent was evaporated. The residue was purified by flash columnchromatography over silica gel (eluent gradient: CH₂Cl₂: hexanes 9:1 upto 100:0; then CH₂Cl₂:CH₃OH:NH₄OH 100:0:0 up to 97:2.7:0.3). The purefractions were collected and the solvent was evaporated. The residue wasdried, yielding 0.73 g of(80.2%)-4-[[5-chloro-4-(2,4,6-trimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile(comp. 6).

Example 2.B6

NaH, 60% suspension in oil (0.003 mol) and 1-methyl-2-pyrrolidinone (3ml) were added to a suspension of 4-hydroxy-3,5-dimethylbenzonitrile(0.003 mol) in 1,4-dioxane (3 ml) in a sealable tube under argon. Afterthe H₂ had evolved, intermediate (11) (0.001 mol) was added. The tubewas sealed and the reaction mixture was heated to 160° C. for 16 hours.The mixture was cooled to room temperature, transferred to a beaker anddiluted with methanol (20 ml). Water (200 ml) was added dropwise. Theaqueous mixture was extracted with CH₂Cl/CH₃OH 90/10 (3×300 ml). Theorganic layer was separated, dried, filtered and adsorbed onto silicagel (1 g). The solvent was evaporated and the residue was purified byflash column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄Hfrom 100/0/0 to 98/1.8/0.2). The desired fractions were collected andthe solvent was evaporated. The residue was triturated with hot CH₃CN,filtered off, then dried, yielding 0.20 g (47.6%) of4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile(comp. 17).

Example 2.B7

To a pressure vessel under argon was added intermediate 12 (0.00286mol), 4-cyano-2,6-dimethylaniline (0.00571 mol), 1M HCl in diethyl ether(0.00140 mol) and 1,4-dioxane (8 ml). The reaction mixture was heated inan oil bath under a stream of nitrogen until all the solvents hadevaporated. 1-methyl-2-pyrrolidinone (3 ml) was added, and the reactionmixture heated at 220-240° C. for 3 hours. Heating was continued at210-220° C. for 6 hours. The residue was dissolved in 1,4-dioxane,evaporated, partitioned between CH₂Cl₂ and 1 N NaOH, filtered, driedorganic layers with potassium carbonate and evaporated. The desiredcompound was isolated and purified by preparative reverse phasechromatography. The pure fractions were collected and the solvent wasevaporated, yielding 0.0165 g (1.1% after lyophilization) of4-[[4-amino-5-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitriletrifluoroacetate (1:1) (comp. 19).

Example 2.B8

A mixture of intermediate (11) (0.0011 mol),2,6-dimethyl-4-(2-propyl)benzenamine (0.0011 mol),N,N,N,N′-tetramethyl-1,8-naphthalenediamine (0.0022 mol) and 1 M HCl inether (2.3 ml) (0.0023 mol) in 1,4-dioxane (25 ml) was stirred andheated to 95° C. for 16 hours. Solvent was removed by rotary evaporationand the residue was purified by reverse phase preparatory HPLC. Thecombined fractions containing the desired material were lyophilized toyield 0.23 g of

(48%); mp. 198-201° C. (comp.)

Example 2.B9

N,N-di(methylethyl)ethanamine (0.0024 mol) was added to4-amino-2,5-dimethyl-3,4-benzonitrile (0.00219 mol) and4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]-benzonitrile (0.00218mol). The reaction vial was sealed and heated to 155-160° C. withstirring for 1.5 days. The sample was cooled to room temperature. Thesample was treated with flash column chromatography over silica gel(eluent: CH₂Cl₂). Purification was completed through preparative HPLC toyield 0.05 g of4-[[5-bromo-4-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(5.0%); mp. 259-260° C.

Example 2.B10

Sequentially 2,4,6-trimethylbenzenamine (0.0022 mol) andN,N-di(methylethyl)-ethanamine (0.0024 mol) were added to a solution ofand 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (0.00218mol) in 1,4-dioxane (10 ml). The tube was sealed and the suspension washeated to 120-130° C. in an oil bath while stirring for 90 hours. Themixture was cooled to room temperature. MoreN,N-di(methylethyl)-ethanamine (15 ml) was added, and the sample wasreheated to 120-130° C. for 64 hours. The reaction was heated at 150° C.for 6 days. The sample was cooled to room temperature. The sample wasdiluted with ethylacetate and extracted with cold 1M NaOH. The aqueousphase was backwashed with ethylacetate. The combined organic phases weredried and concentrated. Flash column chromatography over silica gel(eluent: CH₂Cl₂). The sample was further purified by preparatory HPLC toyield 0.53 g of4-[[5-bromo-4-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]-benzonitrile(54.9%); mp. 220-221° C.

Example 2.B11

A mixture of 4-aminobenzonitrile (0.0043 mol) and

(0.0021 mol) in 1,4-dioxane (30 ml) was stirred at 100° C. for 16 hours.The solvent was removed by rotary evaporation. The solid residue wastriturated and the residue was dried in vacuo at 40° C. for 16 hours,yielding 0.452 g of

(55%); mp.>300° C.

Example 2.B12

To a pressure vessel was added

(0.00567 mol), 4-aminobenzonitrile (0.01163 mol) and1-methyl-2-pyrrolidinone (20 ml). The reaction mixture was heated at140° C. for 16 hours. The reaction mixture was cooled to roomtemperature and acetonitrile and water were added. The resultingprecipitate was filtered, and the solid recrystallized with acetonitrileto give 1.27 g of4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-methyl-2-pyrimidinyl]amino]benzonitrile(52); mp. 260-262° C.

Example 2.B13

Intermediate (11) (0.001 mol) and 2,6-dimethyl-4-aminobenzonitrile(0.00473 mol) were combined and heated to 150° C. while stirring for 16hours. The sample was dissolved in CH₃OH and evaporated onto silica gel(1 g) and eluted with 1:1 hexanes: CH₂Cl₂, 4:1 CH₂Cl₂:hexanes, and neatCH₂Cl₂ (2 L). The desired fractions were evaporated and the residue wasdried in vacuo for 16 hours at 45° C. The thus obtained was transferredto a 4 ml vial in CH₂Cl₂ and the solvent was evaporated, yielding 0.120g of4-[[5-bromo-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]-amino]benzonitrile(28.6%); mp. 277-280° C.

Example 2.B14

4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]-benzonitrile(0.00250 mol) and NH₃/1,4-dioxane 0.5M (0.015 mol) were heated in apressure vessel at 150° C. for 4 days. The sample was allowed to sit atambient conditions for 2 days. Water was added slowly to the mixtureuntil a precipitate formed. The mixture was stirred for 2 hours andfiltered. The solid was recrystallized from CH₃CN to obtain 0.58 g(fraction 1). The filtrate was evaporated (fraction 2). Both fractionswere combined and purified by column chromatography, eluting withCH₂Cl₂. The resulting residue of the desired fraction was recrystallizedfrom CH₃CN to yield 0.44 g of 4-[[4-amino5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile(40.5%). The sample was dried at 80° C. for 16 hours at 0.2 mm Hg.

Example 2.B15

4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]-benzonitrile(0.000660 mol), tetrahydrofuran (1 ml), and 1-pyrrolidineethanamine(0.00198 mol) were added to a pressure vessel. The mixture was heated at75° C. for 16 hours. CH₂Cl₂ was added, and the mixture was washed withwater, dried, filtered and the filtrate was evaporated. Purificationusing flash column chromatography eluting with 1:9 methanol:methylenechloride produced a solid which was redissolved in CH₃CN.HCl/diethylether 1.0 M (0.48 ml) was added, and the mixture was cooledin ice. Filtration yielded 0.19 g of 4-[[5-bromo4-(4-cyano-2,6-dimethylphenoxy)-6-[(1-pyrrolidinyl)ethylamino]-2-pyrimidinyl]amino]benzonitrilehydrochloride (1:1) 3) (50.6%); mp. 208-210° C.

Example 2.B16

To a pressure vessel was added4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile(0.00064 mol), tetrahydrofuran (3 ml), O-methylhydroxylamine (0.06 g),tetrahydrofuran and NaOH 1N (0.00067 mol). The reaction mixture wasstirred for 3 days at room temperature, then for 1 day at 75° C., for 1day at 90° C. and for 2 days at 110° C. To O-methylhydroxylamine (0.60g) was added tetrahydrofuran (4 ml) and NaOH 50% (0.00719 mol). Theliquid was decanted into the reaction flask and the reaction mixture washeated at 110° C. for 3 days. The solvent was evaporated. The residuewas dissolved in CH₂Cl₂, washed with a saturated NaHCO₃ solution andwater, dried (Na₂SO₄), filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 98/2). The pure fractions were collected and the solventwas evaporated. The residue was crystallized from CH₃CN, filtered offand dried, yielding 0.15 g of4-[[5-bromo-4-cyano-2,6-dimethylphenoxy)-6-(methoxyamino)-2-pyrimidinyl]amino]benzonitrile(51%); mp. 185-186° C. The sample was dried (0.2 mm Hg, 80° C., 16hours).

Example 2.B17

a) n-Butyllithium (2.0 l, 0.005 mol) was added to a 0° C. stirredsolution of 1-(methyl-ethyl)-2-propanamine (0.70 ml, 0.005 mol) andtetrahydrofuran (300 ml). After stirring cold for 30 min, compound (17)(0.005 mol) was added. The resulting mixture was stirred cold for 30 minat which point 1,1-dimethylethyl bromoacetate (1.5 ml, 10 mmol) wasadded and the temperature was allowed to rise to room temperature andthe reaction was stirred for three. In a separate flask n-butyllithium(2.0 ml, 5 mmol) was added to a stirred 0° C. solution of1-(methylethyl)-2-propanamine (0.70 ml, 5 mmol) in tetrahydrofuran (50ml) and allowed to react for 30 min at which time it was transferred tothe room temperature reaction. This procedure was repeated. Quenchedwith 0.5 ml H₂O, the sample was concentrated by rotary evaporation ontosilica gel, and purified by flash chromatography (eluting with 0, 10,20% ethylacetate in hexanes) to give a white solid of

mp. 195-197° C.

b) A suspension of compound (17) in 40 ml of N,N-dimethylformamide wastreated with 0.24 g of NaH. The effervescent mixture was stirred for 90.A solution of 1,4-dichloro-1,4-butanedione in 10 mlN,N-dimethylformamide was prepared and cooled in an ice bath. Themixture prepared from compound (17) was transferred to the cold solutionof 1(methylethyl)-1-propanamine and was warmed to room temperature withstirring for 42 hours. Another 0.24 g of NaH was added, the reaction wasstirred for 3 days, and diluted with ether and poured into ice.Precipitation was removed by filtration. The 2 phase filtrate wasseparated and the acidic aqueous fraction was extracted twice more withether. The combined ether fractions were washed with small volumes ofdistilled water and dried. The solvent was evaporated and the residuewas subjected to silica gel column chromatography. Reverse phase prepHPLC with immediate cooling for lyophilization of the appropriatefractions provided 0.07 g of

(7.8%); mp. 232-233° C.

c) To a flask under argon was added NaH 60% and tetrahydrofuran. Thereaction was stirred at room temperature for 10 min and compound (17)added. After stirring for 1 hr ethyl carbonochloridate was added. Thereaction mixture was stirred at room temperature for another 16 hrs andthe solvent evaporated. The residue was partially dissolved indimethylsulfoxide and filtered. The filtrate was purified by reversephase Chromatography and lyophilized to give 0.47 g (18%) of

d) A mixture of4-[[5-amino-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]-amino]benzonitrile(0.00147 mol) in ethanoic acid anhydride (10 ml) and 2-propanone (10 ml)was stirred at room temperature for 16 hours. The mixture was thenheated to 55° C., and more ethanoic acid anhydride (3 ml) was added. Themixture was removed from heat after 18 hours and stirred for 6 days atroom temperature. The sample was concentrated by rotary evaporation to asolid. Purification by column chromatography (eluting with 0, 0.5, 1,1.5, 2% (10% NH₄OH in CH₃OH) in methylene chloride) yielded

mp. 290-295° C. The solid was dried in vacuo for 16 hours at 60° C.

Example 2.B18

A mixture of4-[[4-(4-cyano-2,6-dimethylphenoxy)-5-nitro-2-pyrimidinyl]amino]-benzonitrile(0.0005 mol) in tetrahydrofuran (20 ml) was hydrogenated overnight withPd/C 10% (0.100 g) as a catalyst. After uptake of H₂ (3 equiv; 0.0015mol), the catalyst was filtered off and the filtrate was concentrated byrotary evaporation and dried in vacuo over 16 hours at 40° C., yielding0.15 g of4-[[5-amino-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile(84%); mp.>300° C.

Example 2.B19

4-[[4-[(2,4,6-trimethylphenyl)amino]-5-nitro-2-pyrimidinyl]amino]benzonitrile(0.001 mol), Pd/C 10% (0.025 g), ethanol (20 ml), and hydrazine (0.030mol) were combined to form a slurry and stirred at room temperature for16 hours. The solvent was removed by rotary evaporation. The residue wastaken up in tetrahydrofuran (20 ml) and methanol (1 ml). A secondportion of hydrazine (0.5 g) was added, and the reaction was stirred for16 hours at room temperature. A third portion of hydrazine (0.5 ml) wasadded and the reaction was stirred for an additional 16 hours at roomtemperature. The sample was concentrated by rotary evaporation ontosilica gel (1 g) and purified by flash chromatography (eluent: 0.5, 1,2%10% (NH₄OH in CH₃OH) in CH₂Cl₂). The desired fractions were purified bypreparatory HPLC to yield 0.24 g of4-[[5-amino-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(70%); mp. 224-225° C.

Example 2.B20

Compound (3) (0.001 mol), trimethyl silanecarbonitrile (0.0012 mol),Pd(PPh₃)₂Cl₂ (0.020 g), CuI (0.010 g) and CF₃COO/H₂O (3 ml) werecombined in a sealed tube and heated to 110° C. for 10 hours. Secondportions of the catalysts Pd(PPh₃)₂Cl₂ (0.020 g) and CuI (0.010 g), andCF₃COOH/H₂O (3 ml) were added and the reaction mixture was stirred for10 hours at 110° C. The material was concentrated by rotary evaporation.The residue was purified by preparative reversed-phase HPLC. The desiredfractions were concentrated and purified by reversed-phase preparativeHPLC and dried with a stream of N₂, then in vacuo at 40° C. for 16hours. Yield: 0.011 g of4-[[5-ethynyl-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;mp. 165-175° C.

Example 2.B21

Compound (3) (0.000906 mol), tributylphenyl stannane (0.000906 mol),Pd(PPh₃)₄ (0.002718 mol), and 1,4-dioxane (3 ml) were combined under N₂in a sealed tube and heated to 110° C. for 16 hours. The reactionmixture was cooled and concentrated by rotary evaporation. The samplewas purified by Preparatory Reverse Phase HPLC, then dried under Arstream. Drying in vacuo yielded 0.0845 g of or4-[[5-phenyl-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;mp. 209-214° C.

Example 2.B22

Compound (3) (0.001 mol), tetraethenyl stannane (0.22 ml), 1,4-dioxane(2 ml) and Pd(PPh₃)₄ (0.112 g) were combined in a sealed tube under Ar.The mixture was stirred and heated to 100° C. for 16 hours. Moretetraethenyl stannane and Pd(PPh₃)₄ were added. The reaction was placedunder Ar, stirred and heated. The reaction was concentrated by rotaryevaporation and purified on preparative HPLC. The material was driedwith a N₂ stream, and dried under vacuum for 4 hours at 60° C. to obtain0.422 g of4-[[5-ethenyl-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]-benzonitrile;mp. 237-242° C.

Example 2.B23

Compound (3) (0.001225 mol), CuCN (0.001470 mol) andN,N-dimethylformamide (2 ml) were combined in a sealed tube under Argon,then stirred and heated to 160° C. for 16 hours. The residue waspurified by column chromatography (eluent: CH₂Cl₂/hexane 1/1, then pureCH₂Cl₂). The desired fractions were collected and the solvent wasevaporated. The residue was triturated under CH₂Cl₂ at room temperature.The solid was dried (vacuum, 40° C., 24 hours, yielding 0.0864 g of

(24%); mp. 254-259° C.

Tables 2, 3, 4 and 5 list compounds of formula (I-B) which were madeanalogous to one of the above examples.

TABLE 2

Comp. No. Ex. No. Y Physical data 1 2.Bla Cl — 2 2.Bla Br mp. 227-228°C. 22 2.B11 NO₂ mp. 224-226° C.

TABLE 3

Comp. Ex. No. No. R^(a) R^(b) R^(c) X Y Q 3 2.B1b CH₃ CH₃ CH₃ NH Br Hmp. 227-228° C. 4 2.B2 CH₃ CH₃ CH₃ NH Cl NH₂ mp. 241-242° C. 5 2.B3 CH₃CH₃ CH₃ NH Cl H mp. 224-226° C. 6 2.B5 CH₃ CH₃ CH₃ O Cl H mp. 218-219°C. 7 2.B5 CH₃ CH₃ CH₃ S Cl H mp. 264-266° C. 8 2.B5 CH₃ Br CH₃ O Cl Hmp. 237-238° C. 9 2.B3 CH₃ Br CH₃ NH Cl H mp. 217-219° C. 10 2.B4 Br CH₃Br NH Cl H mp. 262-263° C. 11 2.B4 Br Br F NH Cl H mp. 200-202° C. 122.B4 CH₃ C(CH₃)₃ Cl NH Cl H mp. 214-215° C. 13 2.B4 CH₃ CN CH₃ NH Cl Hmp. 281-283° C. 14 2.B4 Cl Cl CH₃ NH Cl H mp. 243-245° C. 15 2.B5 Cl BrCH₃ O Cl H mp. 244-247° C. 16 2.B5 CH₃ Cl CH₃ O Cl H mp. 232-235° C. 172.B6 CH₃ CN CH₃ O Br H mp. 288-289° C. 18 2.B5 CH₃ CN CH₃ O Cl H mp.283-284° C. 19 2.B7 CH₃ CN CH₃ NH Cl NH₂ mp. 266-268° C. 20 2.B3 Cl ClCH₃ NH Br H mp. 253-254° C. 21 2.B3 CH₃ Br CH₃ NH Br H mp. 243-245° C.23 2.B23 CH₃ CN CH₃ NH CN H mp. 275-290° C. 24 2.B23 CH₃ Br CH₃ NH CN Hmp. 291-299° C. 25 2.B14 CH₃ CN CH₃ O Br NH—CH₃ mp. 248-250° C. 26 2.B14CH₃ CN CH₃ O Br NH₂ mp. 255-256° C. 27 2.B14 CH₃ CH₃ CH₃ O Br NH₂ — 282.B14 CH₃ CH₃ CH₃ O Br NH—CH₃ mp. 213-214° C. 29 2.B14 CH₃ CN CH₃ O BrNH—C₂H₅ mp. 263-264° C. 30 2.B14 CH₃ CN CH₃ O Cl NH₂ mp. 272-274° C. 312.B14 CH₃ CH₃ CH₃ O Cl NH₂ mp. 199-202° C. 32 2.B11 CH₃ CH₃ CH₃ NH NO₂ Hmp. >300° C. 33 2.B5 CH₃ CH₃ CH₃ O Br H mp. 207-215° C. 34 2.B5 CH₃ CH₃CH₃ O Cl Cl mp. 225-226° C. 35 2.B5 CH₃ CN CH₃ O Cl Cl mp. 273-276° C.36 2.B6 CH₃ CN CH₃ O Cl Br mp. 281-282° C. 37 2.B5 CH₃ CH₃ CH₃ O Cl Brmp. 214-215° C.

TABLE 4

Comp. No. Ex. No R^(a) R^(b) R^(c) X Y Q Z 38 2.B17C CH₃ CN CH₃ O Br HC(═O)—CH₃ mp. 194-196° C.

TABLE 5

Comp. No. Ex. No. R^(a) R^(b) X Y Q 39 2.B5 Cl Cl S Br H mp. 198-200° C.

2.C. Pharmacological Example Example 2.C.1

The same test as described above for the compounds of formula (I-A)(example 1.C.1) was used for the in vitro evaluation of the anti-HIVagents of formula (I-B). The compounds of formula (I-B) were shown toinhibit HIV-1 effectively. Particular IC₅₀, CC₅₀ and SI values ofcompounds of formula (I-B) are listed in Table 6 hereinbelow.

TABLE 6 Co. IC₅₀ CC₅₀ Co. IC₅₀ CC₅₀ No. (μM) (μM) SI No. (μM) (μM) SI 20.030 82.6 2730 10 0.005 0.4 92 3 0.006 4.4 738 11 0.002 0.4 183 1 0.00410.9 2787 12 0.020 48.5 2393 4 0.002 10.0 5555 13 0.0005 0.4 860 5 0.0020.4 178 14 0.002 0.4 191 6 0.009 >100 >11049 15 0.010 >100 >9661 70.084 >100 >1182 16 0.010 >100 >10416 8 0.012 >100 >8298 170.002 >10 >6451 9 0.003 1.2 376 18 0.001 >10 >7142

3. Compounds of Formula (I-C)

Hereinafter, the term ‘RT’ means room temperature, ‘THF’ meanstetrahydrofuran and ‘EtOAc’ means ethyl acetate.

3.A. Preparation of the Intermediates Example 3.A1

Starting material 2,4-dichloro-1,3,5-triazine was prepared in 34.8%yield by the method of Synthesis 1981, 907. A solution of2,4-dichloro-1,3,5-triazine (0.0238 mol) in 1,4-dioxane (120 ml) wasprepared with vigorous stirring. 4-Aminobenzonitrile (0.0240 mol) wasadded in one portion, resulting in a suspension. N,N-bis(1-methylethyl)ethanamine (0.0241 mol) was added. The reaction mixture was stirred atRT for 48 hours. The reaction was concentrated in vacuo to produce aviscous orange syrup which was dissolved with EtOAc and treated withcold 1 M NaOH. The combined aqueous phases were back extracted withEtOAc. The combined organic extracts were dried over MgSO₄, filtered andthe filtrate was evaporated to give 5.27 g of yellow powder that wassubjected to flash chromatography on silica gel (eluent: 100% CH₂Cl₂ to90:10 CH₂Cl₂/Et₂O). The pure fractions were collected and the solventwas evaporated to give 3.87 g of off white solid that was recrystallizedfrom CH₃CN, filtered off and dried, yielding 3.57 g (64.8%) of4-[(4-chlor-1,3,5-triazin-2-yl)amino]benzonitrile (Intermediate 1).

3.B. Preparation of the Final Compounds Example 3.B.1

Intermediate (1) (0.00160 mol) was partially dissolved by stirring in1,4-dioxane (10 ml). Sequentially, 2,4,6-trimethylbenzenamine (0.00164mol) and N,N-bis-(1-methylethyl)ethanamine (0.00164 mol) were added, andthe resulting suspension was heated to reflux with stirring. The mixturecleared at 40-50° C. After 4.5 days at reflux, the reaction was cooledto RT, diluted with Et₂O, and treated with cold 1 M NaOH. EtOAc wasadded to dissolve all of the material between the 2 layers. The organicphase was separated and extracted with cold 1 M NaOH. The combinedaqueous fractions were washed with EtOAc, adding solid NaOH to adjustthe pH to >10. The combined organic phases were dried (MgSO₄), filteredand the solvent was evaporated in vacuo to give 0.60 g brown waxy solid.This fraction was purified by flash column chromatography over silicagel (eluent: 100% CH₂Cl₂ to 80:20 CH₂Cl₂/Et₂O). The pure fractions werecollected and the solvent was evaporated to give 0.40 g of white waxysolid that was recrystallized from CH₃CN. The precipitate was filteredoff and dried, yielding 0.24 g (45.4%) of4-[[4-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile(compound 1).

Example 3.B.2

NaH (0.0025 mol) and THF (5 ml) were added to a flask equipped with anaddition funnel. A solution of 2,4,6-trimethylphenol (0.00206 mol) inTHF (15 ml) was added dropwise with stirring over 15 minutes. Thereaction mixture was stirred at room temperature for 45 minutes.Intermediate (1) (0.00203 mol) was added in one portion. The reactionmixture was stirred for 4 days. The reaction was quenched by pouringover ice (75 ml). Upon melting, a minimal amount of precipitate formed.The mixture was treated with Et₂O and EtOAc and the fractions wereseparated. The pH of the aqueous fraction was adjusted to >10 bytreatment with solid NaOH and extracted with EtOAc. The combined organicphases were treated with cold 1 M NaOH. The organic phases were driedover MgSO₄. Concentration in vacuo afforded 0.65 g white powder. Thisfraction was recrystallized from CH₃CN, filtered off and dried, yielding0.50 g (74.4%) of4-[[4-(2,4,6-trimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile(compound 2).

Example 3.B.3

Intermediate (1) (0.00203 mol) and 1,4-dioxane (15 ml) were added to aflask and stirred. Sequentially, 2,4,6-trimethylbenzenethiol (0.00204mol) and N,N-bis(1-methyl-ethyl)ethanamine (0.00207 mol) were added andstirred at ambient temperature. After stirring for one hour, THF (10 ml)was added. The reaction mixture was heated to reflux for 64 hours andcooled to RT. The reaction mixture was diluted with EtOAc and treatedwith cold 1 M NaOH. The aqueous phase was extracted with EtOAc whilemaintaining the pH>10 with the addition of solid NaOH. The combinedorganic phases were dried over MgSO₄ and concentrated to afford 0.75 gyellow powder. The residue was crystallized from CH₃CN, filtered off anddried, yielding 0.64 g (90.7%) of4-[[4-[(2,4,6-trimethylphenyl)thio]-1,3,5-triazin-2-yl]amino]benzonitrile(compound 3).

Table 7 lists the compounds of formula (I-C) which were preparedaccording to one of the above examples.

TABLE 7

Comp No. Ex. No. X R^(a) R^(b) R^(c) Physical Data 1 3.B1 —NH— CH₃ CH₃CH₃ mp. 248-249° C. 2 3.B2 —O— CH₃ CH₃ CH₃ mp. 220-221° C. 3 3.B2 —O—CH₃ Br Cl mp. 221-222° C. 4 3.B3 —S CH₃ CH₃ CH₃ mp. 256-257° C. 5 3.B2—O— Br CH₃ Br mp. 255-257° C. 6 3.B1 —NH— Br CH₃ Br mp. 285-286° C. 73.B1 —NH— CH₃ Br CH₃ mp. 248-249° C.

3.C Pharmacological Example Example 3.C.

The same test as described above for the compounds of formula (I-A)(example 1C.1) was used for the in vitro evaluation of the anti-HIVagents of formula (I-C). The compounds of formula (I-C) were shown toinhibit HIV-1 effectively. Particular IC₅₀, CC₅₀ and SI values ofcompounds of formula (I-C) are listed in Table 8 hereinbelow.

TABLE 8 Co. IC₅₀ CC₅₀ Co. IC₅₀ CC₅₀ No. (μM) (μM) SI No. (μM) (μM) SI 10.0004 9.1 22722 5 0.0016 10.1 6452 2 0.0006 >100 >166666 6 0.0005 1.01901 3 0.0011 56.2 53536 7 0.0007 27.8 39722 4 0.0022 >100 >46511

4. Preparation of the Particles of the Present Invention

8 g of compound 17 of formula (I-A) and 12 g hydroxypropylmethylcellulose 2910 5 mPa·s (HPMC 2910 5 mPa·s) were mixed until themixture was homogenous. The mixture was fed into a Gimac single screwextruder L/D 24:1 having the following operating parameters: screw ratewas 30 revolutions per minute, the temperature ranged from 70° C. to235° C. Yield was 17 g (85%). The melt extrudate was milled andfractions with particle size below 150 μm (condition I in point 6) andbetween 500 and 850 μm (condition II in point 6) were collected.

5. Thermal Stability of the Antiviral Compound in the Melt Extrudate

The thermal stability of compound 17 of formula (I-A) after meltextrusion was determined by HPLC (high performance liquidchromatography). No degradation of the antiviral compound could bedetected, which confirms the thermal stability of said compound aftermelt extrusion.

6. Dissolution Study

In-vitro dissolution studies were performed on the melt extrudatefractions described under point 4. 375 mg of each fraction was directlyadded to the dissolution medium. The fraction with particle size between500 and 850 μm was also filled in a gelatin capsule nr. 0 EL, which wasthen added to the dissolution medium (III). The dissolution medium was900 ml of 0.1 N HCl at 37° C. in Apparatus 2 (USP 23, <711> Dissolution,pp. 1791-1793) (paddle, 100 rpm). The concentration of the activeingredient compound 17 of formula (I-A) dissolved in the test medium wasdetermined by removing a 3 ml sample at the indicated time, filteringthe sample over a millex-LCR filter, measuring its absorbance at 286 nmand calculating the concentration therefrom.

The following results were obtained:

Percentage dissolved active ingredient Time (min) I II III 0 0.00 0.000.00 5 64.32 33.96 12.90 15 76.44 69.18 52.02 30 82.74 79.50 79.08 4591.50 84.84 88.98 60 98.34 92.40 92.28 I: compound 17 of formula (I-A):HPMC 2910 5 mPa · s (1:1.5 (w/w)); fraction with particle size below 150μm II: compound 17 of formula (I-A): HPMC 2910 5 mPa · s (1:1.5 (w/w));fraction with particle size between 500 and 850 μm III: compound 17 offormula (I-A): HPMC 2910 5 mPa · s (1:1.5 (w/w)); fraction with particlesize between 500 and 850 μm filled in a gelatin capsule nr. 0 EL

The in vitro dissolution study from the melt extrudate fractions and thefraction filled in a gelatine capsule shows that the drug releasereached at least 85% after 60 minutes.

1. A particle comprising a solid dispersion comprising (a)4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile,a N-oxide, a pharmaceutically acceptable addition salt, or a quaternaryamine thereof and (b) one or more pharmaceutically acceptablewater-soluble polymers.
 2. The particle according to claim 1 wherein thewater-soluble polymer is a polymer that has an apparent viscosity of 1to 5000 mPa·s when dissolved at 20° C. in an aqueous solution at 2%(w/v).
 3. The particle according to claim 1 wherein the water-solublepolymer is selected from the group consisting of: alkylcelluloses,hydroxyalkylcelluloses, hydroxyalkyl alkylcelluloses,carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses,carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, starches,pectines, chitin derivates, di-, oligo- or polysaccharides, polyacrylicacids and the salts thereof, polymethacrylic acids, the salts and estersthereof, methacrylate copolymers, polyvinylalcohol, polyalkylene oxidesand -copolymers of ethylene oxide and propylene oxide.
 4. The particleaccording to claim 3 wherein the water-soluble polymer is selected fromthe group consisting of methylcellulose; hydroxymethylcellulose;hydroxyethylcellulose; hydroxypropylcellulose; hydroxybutylcellulose;hydroxyethyl methylcellulose; hydroxypropyl methylcellulose;carboxymethylcellulose; sodium carboxymethylcellulose;carboxymethylethylcellulose; sodium carboxymethylamylopectine; chitosan;trehalose; cyclodextrins; alginic acid, alkali metal and ammonium saltsthereof; carrageenans; galactomannans; tragacanth; agar-agar; gummiarabicum; guar gummi; xanthan gummi; polyethylene oxide; polypropyleneoxide; and copolymers of ethylene oxide and propylene oxide.
 5. Theparticle according to claim 3 wherein the water-soluble polymer isselected from poly(butyl methacrylate,(2-dimethylaminoethyl)methacrylate, methyl methacrylate) (1:2:1) andhydroxypropyl methylcellulose.
 6. The particle according to claim 3wherein the water-soluble polymer is poly(butyl methacrylate,(2-dimethylaminoethyl)methacrylate, methyl methacrylate) (1:2:1).
 7. Theparticle according to claim 3 wherein the water-soluble polymer ishydroxypropyl methylcellulose.
 8. The particle according to claim 7wherein the hydroxypropyl methylcellulose has an apparent viscosity fromabout 1 to about 100 mPa·s when dissolved at 20° C. in an aqueoussolution at 2% (w/v).
 9. The particle according to claim 8 wherein thehydroxypropyl methylcellulose has an apparent viscosity from about 3 toabout 15 mPa·s when dissolved at 20° C. in an aqueous solution at 2%(w/v).
 10. The particle according to claim 9 wherein the hydroxypropylmethylcellulose has an apparent viscosity of about 5 mPa·s whendissolved at 20° C. in an aqueous solution at 2% (w/v).
 11. The particleaccording to claim 10 wherein the hydroxypropyl methylcellulose ishydroxypropyl methylcellulose HPMC 2910 5 mPa·s.
 12. The particleaccording to claim 1 wherein the weight-by-weight ratio of (a):(b) is inthe range of 1:1 to 1:899.
 13. The particle according to claim 1 whereinthe weight-by-weight ratio of (a):(b) is in the range of 1:1 to 1:100.14. The particle according to claim 1 wherein the weight-by-weight ratioof (a):(b) is in the range of 1:1 to 1:5.
 15. The particle according toclaim 1 wherein the weight-by-weight ratio of (a):(b) is in the range offrom about 1:1 to about 1:3.
 16. The particle according to claim 1wherein the weight-by-weight ratio of (a):(b) is in the range of about1:3 to about 1:5.
 17. The particle according to claim 1 wherein theweight-by-weight ratio of (a):(b) is in the range of about 1:1 to about1:1.5.
 18. The particle according to claim 1 wherein theweight-by-weight ratio of (a):(b) is in the range of about 1:1.5 toabout 1:3.
 19. The particle according to claim 1 wherein4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile;a N-oxide, a pharmaceutically acceptable addition salt, or a quaternaryamine thereof, is in a non-crystalline phase.
 20. The particle asclaimed in claim 1 wherein the solid dispersion is in the form of asolid solution comprising (a) and (b), or in the form of a dispersionwherein amorphous or microcrystalline (a) or amorphous ormicrocrystalline (b) is dispersed more or less evenly in a solidsolution comprising (a) and (b).
 21. The particle as claimed in claim 1having a particle size of less than 1500 μm.
 22. The particle as claimedin claim 1 having a particle size of less than 250 μm.
 23. The particleas claimed in claim 1 having a particle size of less than 125 μm. 24.The particle as claimed in claim 1 further comprising one or morepharmaceutically acceptable excipients.
 25. A solid dispersioncomprising (a)4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile;a N-oxide, a pharmaceutically acceptable addition salt, or a quaternaryamine thereof; and (b) one or more pharmaceutically acceptablewater-soluble polymers.
 26. The solid dispersion according to claim 25wherein the water soluble polymer is selected from the group consistingof: alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, carboxyalkylcelluloses, alkali metal salts ofcarboxyalkylcelluloses, carboxyalkylalkylcelluloses,carboxyalkylcellulose esters, starches, pectines, chitin derivates, di-,oligo- or polysaccharides, polyacrylic acids and the salts thereof,polymethacrylic acids, the salts and esters thereof, methacrylatecopolymers, polyvinylalcohol, polyalkylene oxides and -copolymers ofethylene oxide and propylene oxide.
 27. The solid dispersion accordingto claim 25 wherein the weight-by-weight ratio of components (a):(b) inthe range of 1:1 to 1:899.
 28. The solid dispersion according to claim25 which is in the form of a solid solution comprising (a) and (b). 29.The solid dispersion according to claim 25 wherein the solid dispersionis in the form of a solid solution comprising (a) and (b), or in theform of a dispersion wherein amorphous or microcrystalline (a) oramorphous or microcrystalline (b) is dispersed more or less evenly in asolid solution comprising (a) and (b).
 30. A pharmaceutical dosage formcomprising a therapeutically effective amount of particles as claimed inclaim
 1. 31. The dosage form according to claim 30 which is a tablet.32. The dosage form according to claim 31 for immediate release of4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]-benzonitrile;a N-oxide, a pharmaceutically acceptable addition salt, or a quaternaryamine thereof; upon oral ingestion wherein said particles arehomogeneously distributed throughout a mixture of a diluent and adisintegrant.
 33. A dosage form according to claim 30 surrounded by afilm-coat comprising a film-forming polymer, a plasticizer andoptionally a pigment.
 34. The dosage form according to claim 32 whereinthe diluent is a spray-dried mixture of lactose monohydrate andmicrocrystalline cellulose (75:25), and the disintegrant is crospovidoneor croscarmellose.
 35. The dosage form according to claim 30 wherein theweight of said particles is at least 40% of the total weight of thedosage form.
 36. The dosage form according to claim 30 containing from200 to 400 mg of4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]-benzonitrile;a N-oxide, a pharmaceutically acceptable addition salt, or a quaternaryamine thereof; per unit dosage form.
 37. The dosage form according toclaim 30 containing from 5 to 200 mg of4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]-benzonitrile;a N-oxide, a pharmaceutically acceptable addition salt, or a quaternaryamine thereof; per unit dosage form.
 38. A process of preparing aparticle according to claim 1 characterized by spray-drying of asolution of the components (a) and (b).
 39. A particle according toclaim 1 consisting of a solid solution comprising two parts by weight of4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile;a N-oxide, a pharmaceutically acceptable addition salt, or a quaternaryamine thereof; and three parts by weight of hydroxypropylmethylcellulose HPMC 2910 5 mPa·s, obtainable by blending saidcomponents, extruding the blend at a temperature in the range of 20°C.-300° C., grinding the extrudate, and optionally sieving the thusobtained particles.
 40. A process of preparing a solid dispersionaccording to claim 25 characterized by (a) spray-drying of a solution ofthe components (a) and (b); (b) preparing a solution of the components(a) and (b), pouring said solution onto a large surface so as to form athin film, and evaporating the solvent therefrom; or (c) melt-extrudingthe components (a) and (b).
 41. A pharmaceutical package suitable forcommercial sale comprising a container, an oral dosage form of4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile;a N-oxide, a pharmaceutically acceptable addition salt, or a quaternaryamine thereof; as claimed in claim 30, and associated with said packagewritten matter.
 42. The particle according to claim 7 wherein theweight-by-weight ratio of (a):(b) is in the range of about 1:1 to about1:3.
 43. The particle according to claim 11 wherein the weight-by-weightratio of (a):(b) is in the range of about 1:1 to about 1:3.
 44. Theparticle according to claim 7 wherein the weight-by-weight ratio of(a):(b) is about 1:3.
 45. The particle according to claim 11 wherein theweight-by-weight ratio of (a):(b) is about 1:3.
 46. A solid dispersionaccording to claim 25 wherein the water-soluble polymer is hydroxypropylmethylcellulose.
 47. A solid dispersion according to claim 25 whereinthe water-soluble polymer is HPMC 2910 mPa·s.
 48. A solid dispersionaccording to claim 46 wherein the weight-by-weight ratio of (a):(b) isin the range of about 1:1 to about 1:3.
 49. A solid dispersion accordingto claim 47 wherein the weight-by-weight ratio of (a):(b) is in therange of about 1:1 to about 1:3.
 50. A solid dispersion according toclaim 46 wherein the weight-by-weight ratio of (a):(b) is about 1:3. 51.A solid dispersion according to claim 47 wherein the weight-by-weightratio of (a):(b) is about 1:3.
 52. The dosage form according to claim 30containing 200 mg of4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile;a N-oxide, a pharmaceutically acceptable addition salt, or a quaternaryamine thereof; per unit dosage form.
 53. The particle according to claim7 wherein (a) is4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile.54. The particle according to claim 11 wherein (a) is4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile.55. The particle according to claim 44 wherein (a) is4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile.56. The particle according to claim 45 wherein (a) is4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile.57. The solid dispersion according to claim 46 wherein (a) is4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile.58. The solid dispersion according to claim 47 wherein (a) is4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile.59. The solid dispersion according to claim 50 wherein (a) is4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile.60. The solid dispersion according to claim 51 wherein (a) is4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile.61. The dosage form according to claim 52 containing 200 mg of4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrileper unit dosage form.
 62. The particle according to claim 1 wherein (a)is4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile.63. The particle according to claim 24 wherein (a) is4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile.64. The particle according to claim 63 wherein the water-soluble polymeris hydroxypropyl methylcellulose.
 65. The particle according to claim 64wherein the water-soluble polymer is HPMC 2910 mPa·s.
 66. The particleaccording to claim 65 wherein the weight-by-weight ratio of (a):(b) isabout 1:3.